Inhibitors of Sodium Glucose Co-Transporter 2 and Methods of Their Use

ABSTRACT

Compounds and pharmaceutical compositions comprising them are disclosed that may be useful for the treatment of diseases and disorders such as diabetes and obesity.

This application claims priority to U.S. provisional application Nos.60/905,714, filed Mar. 8, 2007, and 60/948,780, filed Jul. 10, 2007, theentireties of which are incorporated herein by reference.

1. FIELD OF THE INVENTION

This invention relates to methods of treating metabolic diseases anddisorders such as diabetes, and to compounds and pharmaceuticalcompositions useful therein.

2. BACKGROUND

The sodium glucose co-transporter 2 (SGLT2) is a transporter thatreabsorbs glucose from the renal filtrate and prevents the loss ofglucose in the urine. Because competitive inhibitors of SGLT2 cause therenal excretion of glucose, they may be used to normalize high bloodglucose levels associated with diseases such as diabetes. Handlon, A.L., Expert Opin. Ther. Patents 15(11):1531-1540 (2005).

A number of SGLT2 inhibitors have been disclosed. See, e.g., Handlon,supra; U.S. Pat. No. 6,515,117; U.S. patent application publication nos.US 2006/0035841, US 2004/0138439. At least one inhibitor is in clinicaldevelopment as a treatment for Type 2 diabetes mellitus. See, e.g.,Komoroski, B., et al., “Dapagliflozin (BMS-512148), a SelectiveInhibitor of the Sodium-Glucose Uptake Transporter 2 (SGLT2), ReducesFasting Serum Glucose and Glucose Excursion in Type 2 Diabetes MellitusPatients Over 14 Days” American Diabetes Assn. 67^(th) ScientificSessions, Abstract 0188-OR (2007).

The first known SGLT2 inhibitor was the natural product phlorizin(glucose,1-[2-(β-D-glucopyranosyloxy)-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)-1-propanone),and “all subsequent SGLT2 inhibitors have been glycosides derived fromits structure.” Handlon, supra, at 1533. Phlorizin consists of a glucosemoiety and two hydroxylated aromatic rings joined by a propanone spacer.Ehrenkranz, J. R. L., et al., Diabetes Metab. Res. Rev. 21:31-38 (2005).A review of the patent literature does not reveal any synthetic SGLT2inhibitors that do not contain a glucoside moiety or a derivativethereof. Handlon, supra. In fact, “because of the relative uniformity ofthe glycosides in the SGLT2 patent literature, it has becomeincreasingly difficult for potential drug inventors to find unexploredchemical space.” Id. at 1537. But attempts are still being made. See,e.g., U.S. patent application Ser. No. 11/168,905 to Eckhardt et al.,entitled “D-Xylopyranosyl-Substituted Phenyl Derivatives, MedicamentsContaining Such Compounds, Their Use and Process for Their Manufacture;”Ser. No. 11/182,986 to Eckhardt et al., entitled“Methylidene-D-Xylopyranosyl- and Oxo-D-Xylopyranosyl-Substituted PhenylDerivatives, Medicaments Containing Such Compounds, Their Use andProcess for Their Manufacture;” and Ser. No. 11/199,962 to Eckhardt etal., entitled “D-Xylopyranosyl-Phenyl-Substituted Cycles, MedicamentsContaining Such Compounds, Their Use and Process for Their Manufacture.”

3. SUMMARY OF THE INVENTION

This invention encompasses novel SGLT2 inhibitors. One embodiment of theinvention encompasses compounds of the formula:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted aryl, cycloalkyl, or heterocycle; X is O, S orNR₃; when X is O, R₁ is OR_(1A), SR_(1A), SOR_(1A), SO₂R_(1A) orN(R_(1A))₂; when X is S, R₁ is hydrogen, OR_(1A), SR_(1A), SOR_(1A), orSO₂R_(1A); when X is NR₃, R₁ is OR_(1A), SR_(1A), SOR_(1A), SO₂R_(1A),or R_(1A); each R_(1A) is independently hydrogen or optionallysubstituted alkyl, aryl or heterocycle; R₂ is fluoro or OR_(2A); each ofR_(2A), R_(2B), and R_(2C) is independently hydrogen, optionallysubstituted alkyl, C(O)alkyl, C(O)aryl or aryl; R₃ is hydrogen,C(O)R_(3A), CO₂R_(3A), CON(R_(3B))₂, or optionally substituted alkyl,aryl or heterocycle; each R_(3A) is independently optionally substitutedalkyl or aryl; and each R_(3B) is independently hydrogen or optionallysubstituted alkyl or aryl.

Another embodiment encompasses compounds of the formula:

and pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted aryl, cycloalkyl, or heterocycle; X is O or NR₃;R₂ is fluoro or OR_(2A); each of R_(2A), R_(2B), and R_(2C) isindependently hydrogen, optionally substituted alkyl, C(O)alkyl,C(O)aryl or aryl; R₃ is hydrogen or optionally substituted alkyl, arylor heterocycle; R₈ is hydrogen or C(O)R_(8A); R_(8A) is hydrogen oroptionally substituted alkyl, alkoxy or aryl; R_(9A) and R_(9B) are eachindependently OR_(9C) or SR_(9C), or are taken together to provide O, Sor NR_(9C); and each R_(9C) is independently optionally substitutedalkyl, aryl or heterocycle.

The invention encompasses pharmaceutical compositions comprising thecompounds disclosed herein. The invention also encompasses methods ofinhibiting SGLT2 activity, as well as methods of treating, preventingand managing a variety of diseases and disorders.

4. BRIEF DESCRIPTION OF THE FIGURE

Certain aspects of this invention can be understood with reference toFIG. 1, which shows the effect of various compounds of the invention onthe urine glucose excretion of mice. The compounds were orally dosed at30 mg/kg.

5. DETAILED DESCRIPTION

This invention is based, in part, on the discovery that compounds of theformulae:

the substituents of which are defined below, can inhibit the sodiumglucose co-transporter 2 (SGLT2).

5.1. Definitions

Unless otherwise indicated, the term “alkenyl” means a straight chain,branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or2 to 6) carbon atoms, and including at least one carbon-carbon doublebond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and3-decenyl.

Unless otherwise indicated, the term “alkoxy” means an —O-alkyl group.Examples of alkoxy groups include, but are not limited to, —OCH₃,—OCH₂CH₃, —O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —O(CH₂)₄CH₃, and —O(CH₂)₅CH₃.

Unless otherwise indicated, the term “alkyl” means a straight chain,branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20(e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to4 carbons are referred to as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, ° C.tyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl. Cycloalkyl moieties may be monocyclic ormulticyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and adamantyl. Additional examples of alkyl moieties havelinear, branched and/or cyclic portions (e.g.,1-ethyl-4-methyl-cyclohexyl). The term “alkyl” includes saturatedhydrocarbons as well as alkenyl and alkynyl moieties.

Unless otherwise indicated, the term “alkylaryl” or “alkyl-aryl” meansan alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term “alkylheteroaryl” or“alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term “alkylheterocycle” or“alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.

Unless otherwise indicated, the term “alkynyl” means a straight chain,branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2to 6) carbon atoms, and including at least one carbon-carbon triplebond. Representative alkynyl moieties include acetylenyl, propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or anaromatic or partially aromatic ring system composed of carbon andhydrogen atoms. An aryl moiety may comprise multiple rings bound orfused together. Examples of aryl moieties include, but are not limitedto, anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl,naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, andtolyl.

Unless otherwise indicated, the term “arylalkyl” or “aryl-alkyl” meansan aryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the terms “halogen” and “halo” encompassfluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term “heteroalkyl” refers to an alkylmoiety (e.g., linear, branched or cyclic) in which at least one of itscarbon atoms has been replaced with a heteroatom (e.g., N, O or S).

Unless otherwise indicated, the term “heteroaryl” means an aryl moietywherein at least one of its carbon atoms has been replaced with aheteroatom (e.g., N, O or S). Examples include, but are not limited to,acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl,benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl,imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl,and triazinyl.

Unless otherwise indicated, the term “heteroarylalkyl” or“heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “heterocycle” refers to anaromatic, partially aromatic or non-aromatic monocyclic or polycyclicring or ring system comprised of carbon, hydrogen and at least oneheteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e.,two or more) rings fused or bound together. Heterocycles includeheteroaryls. Examples include, but are not limited to,benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, cinnolinyl, furanyl,hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl,pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl and valerolactamyl.

Unless otherwise indicated, the term “heterocyclealkyl” or“heterocycle-alkyl” refers to a heterocycle moiety bound to an alkylmoiety.

Unless otherwise indicated, the term “heterocycloalkyl” refers to anon-aromatic heterocycle.

Unless otherwise indicated, the term “heterocycloalkylalkyl” or“heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to analkyl moiety.

Unless otherwise indicated, the term “inhibits SGLT2 in vivo” means theinhibition of SGLT2 as determined using the in vivo assay described inthe Examples, below.

Unless otherwise indicated, the terms “manage,” “managing” and“management” encompass preventing the recurrence of the specifieddisease or disorder in a patient who has already suffered from thedisease or disorder, and/or lengthening the time that a patient who hassuffered from the disease or disorder remains in remission. The termsencompass modulating the threshold, development and/or duration of thedisease or disorder, or changing the way that a patient responds to thedisease or disorder.

Unless otherwise indicated, the term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicacids or bases including inorganic acids and bases and organic acids andbases. Suitable pharmaceutically acceptable base addition salts include,but are not limited to, metallic salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc or organic salts madefrom lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. Suitable non-toxic acids include, but are not limited to,inorganic and organic acids such as acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic,glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, phosphoric, propionic, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric,sulfuric, and methanesulfonic acids. Examples of specific salts thusinclude hydrochloride and mesylate salts. Others are well-known in theart. See, e.g., Remington's Pharmaceutical Sciences, 18^(th) ed. (MackPublishing, Easton Pa.: 1990) and Remington: The Science and Practice ofPharmacy, 19^(th) ed. (Mack Publishing, Easton Pa.: 1995).

Unless otherwise indicated, a “potent SGLT2 inhibitor” is a compoundthat has a SGLT2 IC₅₀ of less than about 500 nM.

Unless otherwise indicated, the terms “prevent,” “preventing” and“prevention” contemplate an action that occurs before a patient beginsto suffer from the specified disease or disorder, which inhibits orreduces the severity of the disease or disorder. In other words, theterms encompass prophylaxis.

Unless otherwise indicated, a “prophylactically effective amount” of acompound is an amount sufficient to prevent a disease or condition, orone or more symptoms associated with the disease or condition, orprevent its recurrence. A “prophylactically effective amount” of acompound means an amount of therapeutic agent, alone or in combinationwith other agents, which provides a prophylactic benefit in theprevention of the disease. The term “prophylactically effective amount”can encompass an amount that improves overall prophylaxis or enhancesthe prophylactic efficacy of another prophylactic agent.

Unless otherwise indicated, a “selective SGLT2 inhibitor” is a compoundthat has a SGLT1 IC₅₀ that is at least 10 times greater than its SGLT2IC₅₀.

Unless otherwise indicated, the term “SGLT1 IC₅₀” is the IC₅₀ of acompound determined using the in vitro human SGLT1 inhibition assaydescribed in the Examples, below.

Unless otherwise indicated, the term “SGLT2 IC₅₀” is the IC₅₀ of acompound determined using the in vitro human SGLT2 inhibition assaydescribed in the Examples, below.

Unless otherwise indicated, the term “stereoisomeric mixture”encompasses racemic mixtures as well as stereomerically enrichedmixtures (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and70/30).

Unless otherwise indicated, the term “stereomerically pure” means acomposition that comprises one stereoisomer of a compound and issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure composition of a compound having one stereocenterwill be substantially free of the opposite stereoisomer of the compound.A stereomerically pure composition of a compound having twostereocenters will be substantially free of other diastereomers of thecompound. A typical stereomerically pure compound comprises greater thanabout 80% by weight of one stereoisomer of the compound and less thanabout 20% by weight of other stereoisomers of the compound, greater thanabout 90% by weight of one stereoisomer of the compound and less thanabout 10% by weight of the other stereoisomers of the compound, greaterthan about 95% by weight of one stereoisomer of the compound and lessthan about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

Unless otherwise indicated, the term “substituted,” when used todescribe a chemical structure or moiety, refers to a derivative of thatstructure or moiety wherein one or more of its hydrogen atoms issubstituted with a chemical moiety or functional group such as, but notlimited to, alcohol, aldehyde, alkoxy, alkanoyloxy, alkoxycarbonyl,alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl,alkylcarbonyloxy (—OC(O)alkyl), amide (—C(O)NH-alkyl- or-alkylNHC(O)alkyl), amidinyl (—C(NH)NH-alkyl- or —C(NR)NH₂), amine(primary, secondary and tertiary such as alkylamino, arylamino,arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (—NHC(O)O-alkyl-or —OC(O)NH-alkyl), carbamyl (e.g., CONH₂, as well as CONH-alkyl,CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid,carboxylic acid anhydride, carboxylic acid chloride, cyano, ester,epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl(e.g., —CCl₃, —CF₃, —C(CF₃)₃), heteroalkyl, hemiacetal, imine (primaryand secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxo,phosphodiester, sulfide, sulfonamido (e.g., SO₂NH₂), sulfone, sulfonyl(including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl),sulfoxide, thiol (e.g., sulfhydryl, thioether) and urea(—NHCONH-alkyl-).

Unless otherwise indicated, a “therapeutically effective amount” of acompound is an amount sufficient to provide a therapeutic benefit in thetreatment or management of a disease or condition, or to delay orminimize one or more symptoms associated with the disease or condition.A “therapeutically effective amount” of a compound means an amount oftherapeutic agent, alone or in combination with other therapies, whichprovides a therapeutic benefit in the treatment or management of thedisease or condition. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of a disease or condition, or enhances thetherapeutic efficacy of another therapeutic agent.

Unless otherwise indicated, the terms “treat,” “treating” and“treatment” contemplate an action that occurs while a patient issuffering from the specified disease or disorder, which reduces theseverity of the disease or disorder, or retards or slows the progressionof the disease or disorder.

Unless otherwise indicated, the term “include” has the same meaning as“include, but are not limited to,” and the term “includes” has the samemeaning as “includes, but is not limited to.” Similarly, the term “suchas” has the same meaning as the term “such as, but not limited to.”

Unless otherwise indicated, one or more adjectives immediately precedinga series of nouns is to be construed as applying to each of the nouns.For example, the phrase “optionally substituted alkyl, aryl, orheteroaryl” has the same meaning as “optionally substituted alkyl,optionally substituted aryl, or optionally substituted heteroaryl.”

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.For example, the terms “pyridine” and “pyridyl” are accorded the samemeaning when used to describe a moiety attached to other chemicalmoieties. Thus, the two phrases “XOH, wherein X is pyridyl” and “XOH,wherein X is pyridine” are accorded the same meaning, and encompass thecompounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

It should also be noted that if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or the portion of the structure is to beinterpreted as encompassing all stereoisomers of it. Moreover, any atomshown in a drawing with unsatisfied valences is assumed to be attachedto enough hydrogen atoms to satisfy the valences. In addition, chemicalbonds depicted with one solid line parallel to one dashed line encompassboth single and double (e.g., aromatic) bonds, if valences permit.

5.2. Compounds

One embodiment of this invention encompasses compounds of the formula:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted aryl, cycloalkyl, or heterocycle; X is O, S orNR₃; when X is O, R₁ is OR_(1A), SR_(1A), SOR_(1A), SO₂R_(1A) orN(R_(1A))₂; when X is S, R₁ is hydrogen, OR_(1A), SR_(1A), SOR_(1A), orSO₂R_(1A); when X is NR₃, R₁ is OR_(1A), SR_(1A), SOR_(1A), SO₂R_(1A),or R_(1A); each R_(1A) is independently hydrogen or optionallysubstituted alkyl, aryl or heterocycle; R₂ is fluoro or OR_(2A); each ofR_(2A), R_(2B), and R_(2C) is independently hydrogen, optionallysubstituted alkyl, C(O)alkyl, C(O)aryl or aryl; R₃ is hydrogen,C(O)R_(3A), CO₂R_(3A), CON(R_(3B))₂, or optionally substituted alkyl,aryl or heterocycle; each R_(3A) is independently optionally substitutedalkyl or aryl; and each R_(3B) is independently hydrogen or optionallysubstituted alkyl or aryl.

Particular compounds are of the formula:

Some are of the formula:

Some are of the formula:

One embodiment of the invention encompasses compounds of the formula:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted aryl, cycloalkyl, or heterocycle; B isoptionally substituted aryl, cycloalkyl, or heterocycle; X is O, S orNR₃; Y is O, S, SO, SO₂, NR₄, (C(R₅)₂)_(p),(C(R₅)₂)_(q)—C(O)—(C(R₅)₂)_(q), (C(R₅)₂)_(q)—C(O)O—(C(R₅)₂)_(q),(C(R₅)₂)_(q)—OC(O)—(C(R₅)₂)_(q), (C(R₅)₂)_(q)—C(O)NR₄—(C(R₅)₂)_(q),(C(R₅)₂)_(q)—NR₄C(O)—(C(R₅)₂)_(q), or(C(R₅)₂)_(q)—NR₄C(O)NR₄—(C(R₅)₂)_(q); when X is O, R₁ is OR_(1A),SR_(1A), SOR_(1A), SO₂R_(1A) or N(R_(1A))₂; when X is S, R₁ is hydrogen,OR_(1A), SR_(1A), SOR_(1A), or SO₂R_(1A); when X is NR₃, R₁ is OR_(1A),SR_(1A), SOR_(1A), SO₂R_(1A), or R_(1A); each R_(1A) is independentlyhydrogen or optionally substituted alkyl, aryl or heterocycle; R₂ isfluoro or OR_(2A); each of R_(2A), R_(2B), and R_(2C) is independentlyhydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl, or aryl; R₃is hydrogen, C(O)R_(3A), CO₂R_(3A), CON(R_(3B))₂, or optionallysubstituted alkyl, aryl or heterocycle; each R_(3A) is independentlyoptionally substituted alkyl or aryl; each R_(3B) is independentlyhydrogen or optionally substituted alkyl or aryl; each R₄ isindependently hydrogen or optionally substituted alkyl; each R₅ isindependently hydrogen, hydroxyl, halogen, amino, cyano, OR_(5A),SR_(5A), or optionally substituted alkyl; each R_(5A) is independentlyoptionally substituted alkyl; p is 0-3; and each q is independently 0-2.

Particular compounds are of the formula:

Some are of the formula:

Some are of the formula:

Some are of the formula:

wherein: each R₆ is independently hydrogen, hydroxyl, halogen, amino,cyano, nitro, C≡CR_(6A), OR_(6A), SR_(6A), SOR_(6A), SO₂R_(6A),C(O)R_(6A), CO₂R_(6A), CO₂H, CON(R_(6A))(R_(6A)), CONH(R_(6A)), CONH₂,NHC(O)R_(6A), NHSO₂R_(6A), or optionally substituted alkyl, aryl orheterocycle; each R_(6A) is independently optionally substituted alkyl,aryl or heterocycle; each R₇ is independently hydrogen, hydroxyl,halogen, amino, cyano, nitro, C≡CR_(7A), OR_(7A), SR_(7A), SOR_(7A),SO₂R_(7A), C(O)R_(7A), CO₂R_(7A), CO₂H, CON(R_(7A))(R_(7A)),CONH(R_(7A)), CONH₂, NHC(O)R_(7A), NHSO₂R_(7A), or optionallysubstituted alkyl, aryl or heterocycle; each R_(7A) is independentlyoptionally substituted alkyl, aryl or heterocycle; m is 1-3; and n is1-3.

Some are of the formula:

Some are of the formula:

Some are of the formula:

One embodiment of the invention encompasses compounds of the formula:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted aryl, cycloalkyl, or heterocycle; X is O orNR₃; R₂ is fluoro or OR_(2A); each of R_(2A), R_(2B), and R_(2C) isindependently hydrogen, optionally substituted alkyl, C(O)alkyl,C(O)aryl or aryl; R₃ is hydrogen or optionally substituted alkyl, arylor heterocycle; R₈ is hydrogen or C(O)R_(8A); R_(8A) is hydrogen oroptionally substituted alkyl, alkoxy or aryl; R_(9A) and R_(9B) are eachindependently OR_(9C) or SR_(9C), or are taken together to provide O, Sor NR_(9C); and each R_(9C) is independently optionally substitutedalkyl, aryl or heterocycle.

With regard to the various formulae disclosed herein, as applicable,particular compounds of the invention are such that A is optionallysubstituted 6-membered aryl or heterocycle. In others, A is optionallysubstituted 5-membered heterocycle. In some, A is an optionallysubstituted fused bicyclic heterocycle.

In some, B is optionally substituted 6-membered aryl or heterocycle. Inothers, B is optionally substituted 5-membered heterocycle. In others, Bis an optionally substituted fused bicyclic heterocycle.

In some, X is O. In others, X is S. In others, X is NR₃.

In some, Y is (C(R₄)₂)_(p) and, for example, p is 1. In some, Y is(C(R₅)₂)_(q)—C(O)—(C(R₅)₂)_(q) and, for example, each q is independently0 or 1.

In some, R₁ is OR_(1A). In others, R₁ is SR_(1A). In others, R₁ isSOR_(1A). In others, R₁ is SO₂R_(1A). In others, R₁ is N(R_(1A))₂. Inothers, R₁ is hydrogen. In others, R₁ is R_(1A).

In some, R_(1A) is hydrogen. In others, R_(1A) is optionally substitutedalkyl (e.g., optionally substituted lower alkyl).

In some, R₂ is fluoro. In others, R₂ is OR_(2A).

In some, R_(2A) is hydrogen.

In some, R_(2B) is hydrogen.

In some, R_(2C) is hydrogen.

In some, R₃ is hydrogen. In others, R₃ is optionally substituted loweralkyl (e.g., optionally substituted methyl).

In some, R₄ is hydrogen or optionally substituted lower alkyl.

In some, each R₅ is hydrogen or optionally substituted lower alkyl(e.g., methyl, ethyl, CF₃).

In some, R₆ is hydrogen, hydroxyl, halogen, OR_(6A) or optionallysubstituted lower alkyl (e.g., optionally halogenated methyl, ethyl, orisopropyl). In some, R₆ is hydrogen. In some, R₆ is halogen (e.g.,chloro). In some, R₆ is hydroxyl. In some, R₆ is OR_(6A) (e.g., methoxy,ethoxy). In some, R₆ is optionally substituted methyl (e.g., CF₃).

In some, R₇ is hydrogen, C≡CR_(7A), OR_(7A) or optionally substitutedlower alkyl (e.g., optionally halogenated methyl, ethyl, or isopropyl).In some, R₇ is hydrogen. In some, R₇ is C≡CR_(7A) and R_(7A) is, forexample, optionally substituted (e.g., with lower alkyl or halogen)monocyclic aryl or heterocycle. In some, R₇ is OR_(7A) (e.g., methoxy,ethoxy). In some, R₇ is acetylenyl or optionally substituted methyl orethyl.

Particular compounds of the invention are of the formula:

Others are of the formula:

Others are of the formula:

Others are of the formula:

Others are of the formula:

Others are of the formula:

In particular compounds of formulae I(a)-(d), X is O. In others, X is S.In others, X is NR₃ and R₃ is, for example, hydrogen. In particularcompounds of formulae I(a)-(f), R_(1A) is hydrogen. In others, R_(1A) isoptionally substituted methyl or ethyl.

Preferred compounds are potent SGLT2 inhibitors. Particular compoundshave a SGLT2 IC₅₀ of less than about 500, 400, 300, 250, 200, 150, 100,75, 50 or 25 nM.

Particular compounds are selective SGLT2 inhibitors. For example,certain compounds have a SGLT1 IC₅₀ that is at least 10, 15, 20, 25, 50,75 or 100 times greater than their SGLT2 IC₅₀.

5.3. Methods of Synthesis

Compounds of the invention may be prepared by methods known in the artand by those described herein. For example, compounds may be prepared bymethods such as that shown below in Scheme 1:

In this method, known alcohol 1(a) (see, e.g., Nucleosides Nucleotides,20:649-652 (2001)) is oxidized under suitable conditions (e.g., with anoxidant such as oxalyl chloride in DMSO) to form aldehyde 1(b).Treatment of a bromide of formula 1(c) with an agent such as butyllithium or magnesium bromide followed by addition to aldehyde 1(b)produces alcohol 1(d). Treatment of that compound with an alcohol orwater under acidic conditions produces compound 1(e). If desired,methods well known in the art may be used to transform compound 1(e)into various other compounds encompassed by this invention (e.g.,compounds of formula I, wherein one or more of R_(2A), R_(2B) and R_(2C)is not hydrogen, and/or R₁ is SR_(1A) or NHR_(1A)).

With regard to scheme 1 and other synthetic approaches described herein,methods of preparing the A and A-Y-B moieties are well known, as aremethods of their use to prepare SGLT2 inhibitors. For example, thesynthesis of linked diaryl derivatives in the preparation of SGLT2inhibitors is described in U.S. Pat. Nos. 7,045,665 and 7,053,060; inU.S. patent application Ser. Nos. 10/735,179; 10/745,075; 11/080,150;and 11/182,986; and in international patent application nos. WO2006/006496 and WO 2006/089872.

The synthesis of SGLT2 inhibitors containing linked phenyl-carbocyclemoieties is described, for example, in U.S. patent application Ser. Nos.11/190,315 and 11/199,962.

The synthesis of linked heterocycles and their use to provide SGLT2inhibitors is described, for example, in U.S. patent application Ser.Nos. 10/540,519; 10/734,573; 11/247,216; 11/247,356; and ininternational patent application nos. WO 03/020737; WO 2004/058790; WO2004/080990; WO 2004/089967; WO 2005/011592; WO 2005/012242; WO2005/012243; WO 2005/012318; WO 2005/021566; and WO 2005/085265.

Piperidine-based compounds may be prepared by methods such as that shownbelow in Scheme 2:

In this method, compound 2(a), which may be prepared as shown in Scheme1, is contacted with an azide (e.g., diphenylphosphoryl azide) underconditions sufficient to provide the azide 2(b). The azide is thentreated under acidic conditions to provide the deprotected furan 2(c),which is subsequently treated with a reducing agent (e.g., hydrogen inthe presence of platinum oxide) under acidic conditions to providecompound 2(d). If desired, methods well known in the art may be used totransform compound 2(d) into various other compounds encompassed by thisinvention (e.g., compounds of formula I, wherein one or more of R_(2A),R_(2B) and R_(2C) is not hydrogen, and/or R₁ is SR_(1A) or NHR_(1A)).

Tetrahydrothiopyran-based compounds may be prepared as shown below inScheme 3:

In this method, compound 3(a), which may be prepared as shown in Scheme1, is contacted with a suitable sulfur-containing compound (e.g.,thioacetate) under suitable conditions (e.g., in the presence ofdiethylazodicarboxylate) to form thioacetate 3(b). The thioacetate isthen treated with a suitable base (e.g., cesium hydroxide) to providethe thiol of formula 3(c), which is subsequently treated with an alcoholor water under acidic conditions to provide compound 3(d). If desired,methods well known in the art may be used to transform compound 3(d)into various other compounds encompassed by this invention (e.g.,compounds of formula I, wherein one or more of R_(2A), R_(2B) and R_(2C)is not hydrogen, and/or R₁ is SR_(1A) or NHR_(1A)).

Compounds comprising a fluoronated sugar or sugar analogue (compounds offormula I, wherein R₂ is F) may be prepared from the correspondinglysubstituted starting materials using methods known in the art. See,e.g., U.S. patent application Ser. No. 10/735,179.

Open-form compounds (e.g., compounds of formula II) are readily preparedby methods known in the art. For example, they may be prepared usingapproaches such as that shown below in Scheme 4:

In this method, compound 4(a), which may be prepared as shown in Scheme1, is contacted with a reactive compound (e.g., methylchloroformate)under suitable conditions to form methyl carbonate 4(b). The methylcarbonate is then treated with an alcohol under acidic conditions toprovide compound 4(c). If desired, methods well known in the art may beused to transform compound 4(c) into various other compounds encompassedby this invention (e.g., compounds of formula II, wherein one or more ofR_(2A), R_(2B) and R_(2C) is not hydrogen).

Using methods known in the art, the synthetic approaches shown above arereadily modified to obtain a wide range of compounds. And chiralchromatography and other well-known techniques may be used to obtainstereomerically pure compounds. See, e.g., Jacques, J., et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L.,Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen,S. H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972). Inaddition, syntheses may utilize chiral starting materials to yieldstereomerically enriched or pure products.

5.4. Methods of Use

This invention encompasses a method of inhibiting SGLT2 activity, whichcomprises contacting SGLT2 with an effective amount of a compound of theinvention (i.e., a novel compound disclosed herein). In one embodiment,the protein is in vivo. In another, it is ex vivo.

The invention also encompasses a method of decreasing blood glucose in apatient (e.g., a mammal, such as a human, dog or cat), which comprisesadministering to the patient an effective amount of a compound of theinvention.

The invention also encompasses a method of increasing the excretion ofglucose in the urine of a patient, which comprises administering to thepatient an effective amount of a compound of the invention.

The invention also encompasses a method of restoring or increasinginsulin sensitivity in a patient, which comprises administering to thepatient an effective amount of a compound of the invention.

The invention also encompasses a method of treating, managing orpreventing a disease or disorder in a patient, which comprisesadministering to the patient a therapeutically or prophylacticallyeffective amount of a compound of the invention. Examples of diseasesand disorders include atherosclerosis, cardiovascular disease, diabetes(Type 1 and 2), hyperglycaemia, hypertension, lipid disorders, obesity,and Syndrome X. A particular disease is type 2 diabetes.

The amount, route of administration and dosing schedule of a compoundmay depend upon factors such as the specific indication to be treated,prevented or managed, and the age, gender and condition of the patient.The roles played by such factors are well known in the art, and may beaccommodated by routine experimentation.

5.5. Pharmaceutical Formulations

This invention encompasses pharmaceutical compositions comprising one ormore compounds of the invention. Certain pharmaceutical compositions aresingle unit dosage forms suitable for oral, mucosal (e.g., nasal,sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous,intravenous, bolus injection, intramuscular, or intraarterial), ortransdermal administration to a patient. Examples of dosage formsinclude, but are not limited to: tablets; caplets; capsules, such assoft elastic gelatin capsules; cachets; troches; lozenges; dispersions;suppositories; ointments; cataplasms (poultices); pastes; powders;dressings; creams; plasters; solutions; patches; aerosols (e.g., nasalsprays or inhalers); gels; liquid dosage forms suitable for oral ormucosal administration to a patient, including suspensions (e.g.,aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or awater-in-oil liquid emulsions), solutions, and elixirs; liquid dosageforms suitable for parenteral administration to a patient; and sterilesolids (e.g., crystalline or amorphous solids) that can be reconstitutedto provide liquid dosage forms suitable for parenteral administration toa patient.

The formulation should suit the mode of administration. For example,oral administration requires enteric coatings to protect the compoundsof this invention from degradation within the gastrointestinal tract.Similarly, a formulation may contain ingredients that facilitatedelivery of the active ingredient(s) to the site of action. For example,compounds may be administered in liposomal formulations, in order toprotect them from degradative enzymes, facilitate transport incirculatory system, and effect delivery across cell membranes tointracellular sites.

The composition, shape, and type of a dosage form will vary depending onits use. For example, a dosage form used in the acute treatment of adisease may contain larger amounts of one or more of the activeingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms encompassed by thisinvention will vary from one another will be readily apparent to thoseskilled in the art. See, e.g., Remington's Pharmaceutical Sciences,18^(th) ed. (Mack Publishing, Easton Pa.: 1990).

Pharmaceutical compositions of this invention are preferablyadministered orally. Discrete dosage forms suitable for oraladministration include tablets (e.g., chewable tablets), caplets,capsules, and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18^(th) ed. (Mack Publishing,Easton Pa.: 1990).

Typical oral dosage forms are prepared by combining the activeingredient(s) in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms. If desired, tablets can becoated by standard aqueous or nonaqueous techniques. Such dosage formscan be prepared by conventional methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary. Disintegrants may beincorporated in solid dosage forms to facility rapid dissolution.Lubricants may also be incorporated to facilitate the manufacture ofdosage forms (e.g., tablets).

6. EXAMPLES

Aspects of this invention can be understood from the following examples,which do not limit its scope.

6.1. Example 1 Synthesis of(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol

The captioned compound was prepared in several steps.

A. Preparation of[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-methanol.This compound was synthesized using procedures known in the art. See,e.g., Nucleosides Nucleotides, 20:649-652 (2001) and references therein.

B. Preparation of(3aS,5R,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole-5-carbaldehyde.To a solution of oxalyl chloride (0.76 ml, 8.7 mmol) in CH₂Cl₂ (55 ml)under N₂ at −78° C. was added dropwise a solution of DMSO (0.84 ml, 11.8mmol) in CH₂Cl₂ (5 ml). After 15 minutes, the alcohol from step A (2.40g, 7.9 mmol) in CH₂Cl₂ (20 ml) was added dropwise. After 15 minutes,NEt₃ was added slowly. The reaction was allowed to warm slowly to roomtemperature over 105 minutes, then quenched with H₂O, diluted with Et₂O,and washed with H₂O, sat aq. NaHCO₃, and brine. The combined organicphases were back extracted with Et₂O, which was washed by the samesequence. The combined organic phases were dried of MgSO₄, filtered, andconcentrated under vacuum to give(3aS,5R,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole-5-carbaldehyde(2.4 g, about 64% clean by NMR). The product was carried on withoutfurther purification.

C. Preparation of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene. Thiscompound was prepared as described in U.S. patent application Ser. No.10/745,075 to Deshpande et al., filed Dec. 23, 2003.

D. Preparation of(S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol.To a solution of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene from stepC (3.6 g, 11.1 mmol) in THF (60 ml) under N₂ at −78° C. was addeddropwise BuLi (2.5 M in hexanes, 4.4 ml, 11.1 mmol). After 30 minutes,aldehyde from step B (2.4 g, 64% clean, 5.1 mmol) in THF (20 ml) wasadded dropwise, and the reaction was stirred for 30 min at −78° C.,allowed to warm to room temperature and stirred for 60 minutes, quenchedwith sat. aq. NH₄Cl, diluted with Et₂O, and washed with H₂O and brine.The combined aqueous washes were back extracted with Et₂O, which waswashed by the same sequence. The combined organic extracts were driedover MgSO₄, filtered, and concentrated under vacuum. The residue waspurified by flash chromatography (120 g SiO₂, 0-20% EtOAc: Hexanes, 75minutes, 85 ml/min) to give clean(S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol(0.84 g, 1.5 mmol, 30%) plus the C5 epimer (0.83 g) and some mixedfractions (0.51 g).

¹H NMR (400 MHz, Chloroform-d) δ ppm: 7.37 (d, J=8.34 Hz, 1H), 7.18-7.23(m, 1H), 7.15 (d, J=2.02 Hz, 1H), 7.06-7.11 (m, 2H), 6.80-6.84 (m, 2H),5.99 (d, J=3.79 Hz, 1H), 5.21 (d, J=2.78 Hz, 1H), 5.11 (d, J=2.53 Hz,1H), 4.46 (d, J=3.54 Hz, 1H), 3.97-4.10 (m, 5H), 3.95 (t, J=2.65 Hz,1H), 1.38-1.44 (m, 6H), 1.30 (s, 3H), 0.84 (s, 9H), 0.10 (s, 3H), −0.08(s, 3H).

E. Preparation of(2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol.A solution of 0.35 M HCl in MeOH was prepared by adding AcCl (0.25 ml,3.5 mmol) to MeOH (10 ml) and stirring for 15 minutes The alcohol fromstep D (0.84 g, 1.5 mmol) was treated with this solution for 16 hours atroom temperature and 2 hours at 80° C. in a sealed vial. The reactionwas cooled to room temperature, quenched with K₂CO₃ until basic, dilutedwith CH₂Cl₂, filtered, and concentrated under vacuum. The product waspurified by flash chromatography (40 g SiO₂, 0-10% MeOH: CH₂Cl₂, 60minutes, 35 ml/min), suspended in H₂O, and lyophilized to give(2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol(0.46 g, 1.1 mmol, 75%) as a white solid. NMR revealed a 1.2:1 ratio ofα and β anomers.

¹H NMR (400 MHz, Chloroform-d) δ ppm: 7.38-7.42 (m, 1H), 7.22-7.26 (m,2H), 7.11 (d, J=8.34 Hz, 2H), 6.81-6.85 (m, 2H), 4.86 (d, J=3.79 Hz, 1Hα), 4.43 (d, J=9.85 Hz, 1H α), 4.34 (d, J=7.58 Hz, 1H β), 4.16 (d,J=9.35 Hz, 1H β), 3.99-4.12 (m, 4H), 3.80-3.86 (m, 1H α), 3.64-3.72 (m,1H), 3.54 (s, 3H β), 3.46-3.54 (m, 1.5H), 3.45 (s, 3H α), 2.69 (d,J=2.53 Hz, 1H β), 2.62 (d, J=2.27 Hz, 1H α), 2.50 (d, J=2.27 Hz, 1H β),2.12 (d, J=9.85 Hz, 1H α), 2.00 (d, J=3.03 Hz, 1H β), 1.98 (d, J=2.78Hz, 1H α), 1.41 (t, J=6.95 Hz, 3H). MS (ES+) [M+NH₄]⁺=426.

6.2. Example 2 Synthesis of(3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol

The alcohol from Example 1, step D (51 mg, 0.093 mmol) was treated with1:1 AcOH:H₂O (1 ml) at 80° C. in a sealed vial for 18 hours. Thereaction was cooled to room temperature, diluted with EtOAc to transferto a flask, and concentrated under vacuum. The residue was dissolved inCH₂Cl₂, treated with NaHCO₃ and MgSO₄ for 30 minutes, filtered, andconcentrated under vacuum. The product was purified by flashchromatography (4 g SiO₂, 0-12% MeOH: CH₂Cl₂, 30 minutes, 10 ml/min),suspended in H₂O, and lyophilized to give(3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol(31 mg, 0.079 mmol, 85%) as a white solid. NMR revealed a 1:1 ratio of αand β anomers.

¹H NMR (400 MHz, methanol-d₄) δ ppm 7.34 (dd, J=8.08, 4.04 Hz, 1H),7.22-7.30 (m, 2H), 7.09 (d, J=8.34 Hz, 2H), 6.80 (d, J=8.08 Hz, 2H),5.16 (d, J=3.79 Hz, 1H α), 4.65 (d, J=9.60 Hz, 1H α or β), 4.59 (d,J=7.58 Hz, 1H α or β), 4.14 (d, J=9.60 Hz, 1H α or β), 3.96-4.07 (m,4H), 3.76 (t, J=9.35 Hz, 1H α or β), 3.50 (dd, J=9.60, 3.79 Hz, 1H α orβ), 3.43 (t, J=9.09 Hz, 1H α or β), 3.23-3.29 (m, 1.5H), 1.36 (t, J=7.07Hz, 3H). MS (ES+) [M+NH₄]⁺=412.

6.3. Example 3 Synthesis of(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethoxy-tetrahydro-pyran-3,4,5-triol

A solution of 0.35 M HCl in EtOH was prepared by adding AcCl (0.025 ml,0.35 mmol) to EtOH (1 ml) and stirring for 15 minutes The alcohol fromExample 1, step D (61 mg, 0.11 mmol) was treated with this solution for2 hours at 80° C. in a sealed vial. The reaction cooled to roomtemperature, quenched with concentrated NH₄OH until basic, treated withNaHCO₃ for 30 minutes, diluted with CH₂Cl₂, filtered, and concentratedunder vacuum. The product was purified by flash chromatography (4 gSiO₂, 0-10% MeOH: CH₂Cl₂, 40 minutes, 10 ml/min), suspended in H₂O, andlyophilized to give(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethoxy-tetrahydro-pyran-3,4,5-triol(40 mg, 0.095 mmol, 85%) as a white solid. NMR revealed a 1.75:1 ratioof α and β anomers.

¹H NMR (400 MHz, Chloroform-d) δ ppm: 7.28-7.32 (m, 1H), 7.14 (m, 2H),7.02 (d, J=8.84 Hz, 2H), 6.72-6.76 (m, 2H), 4.88 (d, J=4.04 Hz, 1H α),4.37 (d, J=9.60 Hz, 1H α), 4.33 (d, J=7.83 Hz, 1H β), 4.06 (d, J=9.35Hz, 1H β), 3.89-4.02 (m, 4H), 3.36-3.87 (m, 5H), 2.62 (s, 1H β), 2.54(s, 1H α), 2.41 (d, J=1.52 Hz, 1H β), 2.02 (d, J=10.36 Hz, 1H α), 1.92(d, J=2.53 Hz, 1H), 1.32 (t, J=6.95 Hz, 3H), 1.13-1.19 (m, 3H). MS (ES+)[M+NH₄]⁺=440.

6.4. Example 4 Synthesis of(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-isopropoxy-tetrahydro-pyran-3,4,5-trioland(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-isopropoxy-tetrahydro-pyran-3,4,5-triol

A solution of 0.35 M HCl in i-PrOH was prepared by adding AcCl (0.025ml, 0.35 mmol) to i-PrOH (1 ml) and stirring for 15 minutes The alcoholfrom Example 1, step D (68 mg, 0.12 mmol) was treated with this solutionfor 2 hours at 80° C. in a sealed vial. The reaction cooled to roomtemperature, quenched with concentrated NH₄OH until basic, treated withNaHCO₃ for 30 minutes, diluted with CH₂Cl₂, filtered, and concentratedunder vacuum. The residue was purified by flash chromatography (4 gSiO₂, 0-10% MeOH: CH₂Cl₂, 40 minutes, 10 ml/min) to give 50 mg ofmaterial, which was further purified by prep HPLC (19×50 mm C18 column,20-70% MeCN:H₂O (10 mM NH₄OAc), 14 minutes, 30 ml/min) to give(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-isopropoxy-tetrahydro-pyran-3,4,5-triol(β anomer, 7 mg, 0.016 mmol) and(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-isopropoxy-tetrahydro-pyran-3,4,5-triol(α anomer, 25 mg, 0.057 mmol).

(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-isopropoxy-tetrahydro-pyran-3,4,5-triol:¹H NMR (400 MHz, Chloroform-d) δ ppm: 7.37-7.40 (m, 1H), 7.26 (m, 2H),7.12 (d, J=8.59 Hz, 2H), 6.80-6.84 (m, 2H), 4.48 (d, J=7.83 Hz, 1H),4.15 (d, J=9.35 Hz, 1H), 3.95-4.10 (m, 5H), 3.69 (t, J=9.09 Hz, 1H),3.46-3.52 (m, 2H), 2.69 (br. s., 1H), 2.43 (br. s., 1H), 2.05 (br. s.,1H), 1.41 (t, J=7.07 Hz, 3H), 1.22 (t, J=6.57 Hz, 6H). MS (ES+)[M+NH₄]⁺=454.

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-isopropoxy-tetrahydro-pyran-3,4,5-triol:¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.84 Hz, 1H), 7.22 (m,2H), 7.11 (d, J=8.59 Hz, 2H), 6.80-6.85 (m, 2H), 5.04 (d, J=4.04 Hz,1H), 4.51 (d, J=9.60 Hz, 1H), 3.98-4.10 (m, 4H), 3.93 (ddd, J=12.25,6.32, 6.19 Hz, 1H), 3.82 (t, J=9.22 Hz, 1H), 3.62 (dd, J=9.47, 3.66 Hz,1H), 3.49 (t, J=9.22 Hz, 1H), 2.03 (br s, 3H), 1.41 (t, J=6.95 Hz, 3H),1.23 (d, J=6.32 Hz, 3H), 1.19 (d, J=6.06 Hz, 3H). MS (ES+) [M+NH₄]⁺=454.

6.5. Example 5 Synthesis of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-trioland(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol

A sample of compound from Example 1 step E (80 mg) was dissolved in 4 mlof 30% ethanol/hexanes and injected in 400 μl portions onto a ChiralPakAD-H column (20×250 mm, 5.5 ml/min, 31.55% ethanol/hexane as eluentisocratic, ambient temperature, 30 min run) to separate the two isomersfrom each other. The first isomer (r.t. 23 min) was identified as thealpha isomer (6R, 20 mg) and the second (r.t. 26 minutes, 21 mg) wasidentified as the beta isomer (6S).

(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol:¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.84 Hz, 1H), 7.22-7.25(m, 2H), 7.11 (d, J=8.59 Hz, 2H), 6.83 (d, J=8.59 Hz, 2H), 4.85 (d,J=4.04 Hz, 1H), 4.42 (d, J=9.60 Hz, 1H), 3.99-4.11 (m, 4H), 3.82 (t,J=9.22 Hz, 1H), 3.66 (br. s., 1H), 3.42-3.48 (m, 4H), 2.79 (br. s., 1H),2.23 (d, J=1.26 Hz, 1H), 2.12 (br. s., 1H), 1.40 (t, J=6.95 Hz, 3H). MS(ES+) [M+NH₄]⁺=426.

(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol:¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.59 Hz, 1H), 7.23-7.26(m, 2H), 7.11 (d, J=8.84 Hz, 2H), 6.80-6.84 (m, 2H), 4.33 (d, J=7.58 Hz,1H), 4.07-4.17 (m, 2H), 3.98-4.04 (m, 3H), 3.68 (t, J=9.09 Hz, 1H),3.46-3.55 (m, 5H), 2.89 (br. s., 1H), 2.64 (br. s., 1H), 2.16 (br. s.,1H), 1.40 (t, J=7.07 Hz, 3H). MS (ES+) [M+NH₄]⁺=426.

(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triolwas also synthesized selectively using the following procedure:

A. Preparation of acetic acid(3S,4R,5S,6S)-2,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-ylester. The alcohol from Example 1, step D (6.80 g, 12.4 mmol) wastreated with 3:2 AcOH/H₂O (62 ml) at 100° C. for 22 hours. The reactionwas concentrated under vacuum, rotovapped 3 times with toluene, andplaced under high vacuum. The residue was treated with acetic anhydride(9.4 ml, 99.2 mmol) in pyridine (25 ml) for 16 hours. The reaction wasquenched with H₂O, stirred 1 hour, diluted with Et₂O, washed with 1 Maq. NaHSO₄, H₂O, sat. aq. NaHCO₃, and brine (with back extraction),dried over MgSO₄, filtered, and concentrated under vacuum. The residuewas purified by flash chromatography (120 g SiO₂, 0-50% EtOAc/Hex) togive acetic acid(3S,4R,5S,6S)-2,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-ylester (6.10 g, 10.9 mmol, 87%).

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.36 (dd, J=8.08, 2.02 Hz, 1H),7.19 (dt, J=8.34, 2.02 Hz, 1H), 7.07-7.09 (m, 1H), 7.06 (dd, J=8.72,1.64 Hz, 2H), 6.83 (d, J=8.59 Hz, 2H), 6.44 (d, J=3.54 Hz, 0.5H α), 5.84(d, J=8.08 Hz, 0.5H), 5.55 (t, J=9.98 Hz, 0.5H α), 5.33 (t, J=9.71 Hz,0.5H β), 5.20-5.27 (m, 1H), 5.09 (t, J=9.60 Hz, 0.5H β), 5.03 (t, J=9.73Hz, 0.5H α), 4.78 (d, J=10.11 Hz, 0.5H α), 4.47 (d, J=9.85 Hz, 0.5H),3.94-4.09 (m, 4H), 2.20 (s, 1.5H α), 2.11 (s, 1.5H β), 2.06 (s, 1.5H β),2.05 (s, 1.5H α), 2.02 (s, 1.5H α), 2.01 (s, 1.5H β), 1.74 (s, 1.5H α),1.72 (s, 1.5H β), 1.41 (t, J=6.95 Hz, 3H). MS (ES+) [M+NH₄]⁺=580.

B. Preparation of acetic acid(2S,3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-ylester. The tetraacetate of step A (8.08 g, 14.4 mmol) was treated with33% HBr in AcOH (30 ml) for 1 hour. The reaction was diluted with CH₂Cl₂(60 ml), stirred for 30 minutes, diluted with more DCM, washed 3× withice cold H₂O and with sat. aq. NaHCO₃ (with back extraction), dried overMgSO₄, filtered, and concentrated under vacuum to give acetic acid(2S,3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-ylester.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.37 (d, J=8.34 Hz, 1H), 7.17 (dd,J=8.21, 2.15 Hz, 1H), 7.12 (d, J=2.27 Hz, 1H), 7.06 (d, J=8.59 Hz, 2H),6.83 (d, J=8.59 Hz, 2H), 6.71 (d, J=4.04 Hz, 1H), 5.64 (t, J=9.73 Hz,1H), 5.10 (t, J=9.73 Hz, 1H), 4.92-4.98 (m, 2H), 3.94-4.11 (m, 4H), 2.13(s, 3H), 2.03 (s, 3H), 1.74 (s, 3H), 1.41 (t, J=7.07 Hz, 3H). MS (ES+)[M+NH₄]⁺=602.

C. Preparation of acetic acid(2S,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-ylester. Crude bromide from step B (8.4 g, 14.4 mmol) and ZnO (1.2 g, 14.4mmol) were dissolved in MeOH (144 ml) and heated at 70° C. for 1 hour.The reaction was cooled to room temperature, filtered through celitewith EtOAc, and concentrated under vacuum. The residue wasrecrystallized from MeOH in two batches to give acetic acid(2S,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-ylester (5.98 g, 11.2 mmol, 78%) as the pure β-anomer.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.37 (d, J=8.08 Hz, 1H), 7.22 (dd,J=8.21, 2.15 Hz, 1H), 7.05-7.10 (m, 3H), 6.80-6.85 (m, 2H), 5.29 (t,J=9.47 Hz, 1H), 5.11 (dd, J=9.73, 7.96 Hz, 1H), 5.02 (t, J=9.73 Hz, 1H),4.54 (d, J=8.08 Hz, 1H), 4.33 (d, J=9.85 Hz, 1H), 3.96-4.09 (m, 4H),3.49 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.71 (s, 3H), 1.41 (t, J=6.95Hz, 3H). MS (ES+) [M+NH₄]⁺=552.

D. Preparation of(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol.Recrystallized triacetate from step C (5.98 g, 11.2 mmol) was treatedwith K₂CO₃ (7.7 g, 56 mmol) in MeOH (112 ml) with vigorous stirring for1 hour. The reaction was filtered through celite and concentrated undervacuum. The residue was dissolved in DCM, washed with H₂O and brine,dried over MgSO₄, filtered, and concentrated under vacuum. The residuewas passed through a plug of silica gel with 5% MeOH:CH₂Cl₂,concentrated under vacuum, suspended in H₂O, and lyophilized to give(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol(4.37 g, 10.7 mmol, 96%) as a white solid.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.59 Hz, 1H), 7.23-7.27(m, 2H), 7.11 (d, J=8.59 Hz, 2H), 6.82 (d, J=8.59 Hz, 2H), 4.33 (d,J=7.83 Hz, 1H), 4.15 (d, J=9.35 Hz, 1H), 3.98-4.12 (m, 4H), 3.68 (t,J=9.09 Hz, 1H), 3.53 (s, 3H), 3.46-3.53 (m, 2H), 2.80 (br. s., 1H), 2.58(br. s., 1H), 2.09 (br. s., 1H), 1.40 (t, J=7.07 Hz, 3H). MS (ES+)[M+NH₄]⁺=426.

6.6. Example 6 Synthesis ofN-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yl}-N-propyl-acetamide

The bromide from Example 5, step B (58 mg, 0.1 mmol) was treated withpropylamine (0.1 ml) in CH₂Cl₂ (0.5 ml) at 40° C. for 1.5 hours. Thereaction was blown down with N₂, then blown down 2 times from CH₂Cl₂.The residue was treated with acetic anhydride (78 μl, 0.82 mmol) inpyridine (1 ml) overnight. The reaction was quenched with MeOH, stirredfor 30 minutes, diluted with Et₂O, washed with 1 M aq. NaHSO₄, H₂O, sat.aq. NaHCO₃, and brine (with back extraction), dried over MgSO₄,filtered, and concentrated under vacuum. The intermediate was treatedwith K₂CO₃ (14 mg, 0.10 mmol) in MeOH (1 ml) for 1.5 hours. The reactionwas filtered and concentrated under vacuum, and the residue was purifiedby flash chromatography (12 g SiO₂, 0-10% MeOH:CH₂Cl₂) to give 90% purematerial. The product was further purified by HPLC (19×50 mm C18 column,20-70% MeCN:H₂O (10 mM NH₄OAc), 14 minutes, 30 ml/min), suspended inH₂O, and lyophilized to giveN-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yl}-N-propyl-acetamide(3 mg, 0.0063 mmol, 15%) as a 2:1 ratio of rotamers.

¹H NMR (400 MHz, MeOD) δ ppm 7.29-7.40 (m, 1H), 7.16-7.26 (m, 2H), 7.08(d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.59 (d, J=8.6 Hz, 0.33H),4.98 (d, J=11.9 Hz, 0.67H), 4.25 (d, J=9.3 Hz, 0.67H), 4.17 (d, J=9.9Hz, 0.33H), 3.92-4.06 (m, 4H), 3.46-3.64 (m, 3H), 3.06-3.28 (m, 2H),2.16 (s, 3H), 1.49-1.68 (m, 2H), 1.36 (t, J=6.9 Hz, 3H), 0.93 (t, J=7.5Hz, 1H), 0.87 (t, J=7.5 Hz, 2H). MS (ES+) [M+H]+=478.

6.7. Example 7 Synthesis of(2R,3S,4S,5S)-5-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-2,3,4,5-tetrahydroxy-pentanaloxime

Compound from Example 2 (50 mg, 0.13 mmol) and hydroxylaminehydrochloride (26 mg, 0.38 mmol) were dissolved in pyridine (0.65 ml)and stirred for 3 hours. The reaction was diluted with EtOAc, washedwith 1 M aq. NaHSO₄, H₂O, sat. aq. NaHCO₃, and brine (with backextraction), dried over Na₂SO₄, filtered, and concentrated under vacuum.The residue was suspended in H₂O and lyophilized to give(2R,3S,4S,5S)-5-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-2,3,4,5-tetrahydroxy-pentanaloxime (46 mg, 0.11 mmol, 88%) as a 5:1 mixture of oxime isomers.

Major isomer ¹H NMR (400 MHz, MeOD) δ ppm 7.31-7.36 (m, 2H), 7.23-7.30(m, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 4.63 (d, J=8.1Hz, 1H), 4.28 (t, J=6.8 Hz, 1H), 3.96-4.03 (m, 4H), 3.90-3.94 (m, 1H),3.59 (dd, J=8.0, 1.6 Hz, 1H), 1.36 (t, J=6.9 Hz, 3H); MS (ES+)[M+H]⁺=410.

6.8. Example 8 Synthesis of(3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-oneoxime

A. Preparation of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxy-tetrahydro-pyran-3-ylester. The tetraacetate from Example 5, step A (200 mg, 0.36 mmol) wastreated with benzylamine (39 μl, 0.36 mmol) in DMF (1.8 ml) for 2 hours.The reaction diluted with Et₂O, washed with 1 M aq. NaHSO₄, H₂O, sat.aq. NaHCO₃, and brine, dried over MgSO₄, filtered, and concentratedunder vacuum. The residue was purified by flash chromatography (12 gSiO₂, 0-50% EtOAc:Hex.) to give acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxy-tetrahydro-pyran-3-ylester (142 mg, 0.27 mmol, 77%) as a 3:1 ratio of anomers.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.33-7.40 (m, 1H), 7.18-7.23 (m,1H), 7.09-7.14 (m, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H),5.59-5.66 (m, 0.75H), 5.56 (t, J=3.7 Hz, 0.75H), 5.34 (t, J=9.6 Hz,0.25H), 4.90-5.11 (m, 2.75H), 4.86 (t, J=8.2 Hz, 0.25H), 4.39 (d, J=9.9Hz, 0.25H), 3.93-4.10 (m, 4H), 3.36 (d, J=8.6 Hz, 0.25H), 2.81 (dd,J=3.8, 1.3 Hz, 0.75H), 2.12 (s, 0.75H), 2.12 (s, 2.25H), 2.02 (s,0.75H), 2.01 (s, 2.25H), 1.73 (s, 2.25H), 1.72 (s, 0.75H), 1.41 (t,J=7.1 Hz, 3H); MS (ES+) [M+NH₄]⁺=538.

B. Preparation of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-[(Z)-hydroxyimino]-tetrahydro-pyran-3-ylester. Compound from step A (142 mg, 0.27 mmol) and hydroxylaminehydrochloride (57 mg, 0.82 mmol) were dissolved in pyridine (1.4 ml).The reaction was stirred for 6 hours, diluted with EtOAc, washed with 1M aq. NaHSO₄, H₂O, sat. aq. NaHCO₃, and brine (with back extraction),dried over Na₂SO₄, filtered, and concentrated under vacuum. The residuewas dissolved in CH₂Cl₂, cooled to −78° C., and treated with DBU (49 μL,0.33 mmol) followed by N-chlorosuccinimide (44 mg, 0.33 mmol). Thereaction was stirred for 20 minutes at −78° C., then allowed to warm toroom temperature over 15 minutes The reaction was diluted with EtOAc,washed with H₂O and brine (with back extraction), dried over MgSO₄,filtered, and concentrated under vacuum. The residue was purified byflash chromatography (12 g SiO₂, 0-50% EtOAc:Hex.) to give acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-[(Z)-hydroxyimino]-tetrahydro-pyran-3-ylester (97 mg, 0.18 mmol, 67%).

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.42 (d, J=8.1 Hz, 1H), 7.30 (dd,J=8.2, 2.1 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.83(d, J=8.6 Hz, 2H), 6.64 (s, 1H), 5.53 (d, J=4.5 Hz, 1H), 5.28 (dd,J=5.8, 4.5 Hz, 1H), 5.16-5.22 (m, 1H), 5.10-5.15 (m, 1H), 3.98-4.10 (m,4H), 2.19 (s, 3H), 2.07 (s, 3H), 1.78 (s, 3H), 1.41 (t, J=7.1 Hz, 3H);MS (ES+) [M+H]⁺=534.

C. Preparation of(3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-oneoxime. Compound from step B (97 mg, 0.18 mmol) was treated with 7.0 MNH₃ in MeOH (1.8 ml) for 1 hour. The reaction was concentrated undervacuum, and the residue was purified by flash chromatography (12 g SiO₂,0-12% MeOH:CH₂Cl₂), suspended in H₂O, and lyophilized to give(3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-oneoxime (57 mg, 0.14 mmol, 77%) as a white solid.

¹H NMR (400 MHz, MeOD) δ ppm 7.36-7.44 (m, 2H), 7.31-7.35 (m, 1H), 7.12(d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 4.91-4.95 (m, 1H), 4.14 (d,J=5.6 Hz, 1H), 4.03-4.10 (m, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.73-3.78 (m,1H), 3.55 (dd, J=9.9, 6.6 Hz, 1H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+)[M+H]⁺=408.

6.9. Example 9 Synthesis of(2S,3R,4R,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-5-fluoro-6-methoxy-tetrahydro-pyran-3,4-diol

A. Preparation of(2S,3R,4S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4-dihydro-2H-pyran-3,4-diyldiacetate. To a flask charged with 282 mg of tetraacetate from Example5, step A (0.5 mmol), 1.25 ml of HBr (33% in HOAc) was added. Thereaction was stirred for one hour, diluted with 50 ml dichloromethaneand quenched by pouring into ice water. The organic layer was separatedand washed with saturated aqueous NaHCO₃ and brine. After drying overmagnesium sulfate, the solvents were concentration in vacuo. The cruderesidue was taken up in 0.5 ml dichloromethane and added to a suspensionof copper(II) sulfate (20 mg, 0.125 mmol), Zn powder (82 mg, 1.25 mmol),and sodium acetate (984 mg, 12 mmol) in 2.5 ml acetic acid/water (3:2v:v). This mixture was allowed to stir at room temperature for 4 h,after which the reaction was recharged with 20 mg copper(II) sulfate and82 mg Zn powder and stirred for another 18 h. The mixture was quenchedwith water, extracted with ethyl acetate. The organic layer was driedover magnesium sulfate and removed in vacuo. Flash chromatographyprovided(2S,3R,4S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4-dihydro-2H-pyran-3,4-diyldiacetate (32 mg, 16% yield).

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.36 (d, J=8.08 Hz, 1H), 7.20 (dd,J=8.08, 2.27 Hz, 1H), 7.16 (d, J=2.27 Hz, 1H), 7.08 (d, J=8.59 Hz, 2H),6.82 (d, J=8.59 Hz, 2H), 6.57 (dd, J=6.06, 1.52 Hz, 1H), 5.54 (ddd,J=7.07, 2.53, 1.52 Hz, 1H), 5.32 (dd, J=9.60, 7.07 Hz, 1H), 4.83-4.88(m, 1H), 4.01 (q, J=6.82 Hz, 2H), 3.96-4.10 (m, 2H), 1.96 (s, 3H), 1.77(s, 3H), 1.40 (t, J=6.82 Hz, 3H). MS (ES+) [M+NH4]+=462.

B. Preparation of(2S,3R,4R,5R,6R)-2-(4-chloro-3-(4-ethoxy-benzyl)-phenyl)-5-fluoro-6-methoxy-tetrahydro-2H-pyran-3,4-diol.Selectfluor™ (45 mg, 0.128 mmol) was added to a solution of compoundfrom step A (38 mg, 0.0853 mmol) in 0.4 mL acetonitrile:methanol (1:1v:v). The reaction was stirred at ambient temperature and monitored forcompletion by LCMS. The reaction was quenched with 2 mL saturatedaqueous NH4Cl and extracted with diethyl ether (2×5 mL). The organicextracted were dried over sodium sulfate and concentrated in vacuo.Flash chromatography (5 to 10% ethyl acetate/hexanes) provided thefluorinated product. Potassium carbonate (5 mg) was then added to asolution of this isolated product in 0.5 mL of methanol. The reactionwas stirred at ambient temperature for 2 h, after which it was quenchedwith 2 mL water and extracted with ethyl acetate (2×4 mL). The organiclayer was filtered over a pad of silica and concentrated to provide 6.3mg of(2S,3R,4R,5R,6R)-2-(4-chloro-3-(4-ethoxy-benzyl)-phenyl)-5-fluoro-6-methoxy-tetrahydro-2H-pyran-3,4-diolas a clear oil.

¹H NMR (400 MHz, Chloroform-d, 3:2 α:β anomeric ratio, 2:1axial:equatorial fluorine ratio, isomers due to the minor equatorialfluorine structure is noted in italics) δ ppm 7.41 (dd, J=8.34, 2.78 Hz,1H), 7.20-7.33 (m, 2H), 7.11 (d, J=8.59 Hz, 2H), 6.83 (d, J=8.59 Hz,2H), 4.92-5.02 (m, 1H), 4.30-4.52 (m, 1H), 3.96-4.27 (m, 6H), 3.74 (t,J=9.09 Hz, 0.66Hα), 3.57/3.56 (s, 3H), 3.49 (t, J=9.09 Hz, 0.33Hβ),3.42/3.41 (s, 3H). MS (ES+) [M+NH₄]⁺=428.

6.10. Example 10 Synthesis of(2S,3R,4R,5S)-2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol

A. Preparation of[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane. Thiscompound was prepared as described in U.S. patent applicationpublication no. 2006/0251728 to Himmelsbach et al., published Nov. 9,2006.

B.(S)-{3-[4-(tert-butyl-dimethyl-silanyloxy)-benzyl]-4-chloro-phenyl}-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-methanol.A solution of 0.85 g (2.07 mmol) compound from step A in 4.14 ml diethylether was cooled to −78° C. under an inert atmosphere. To this was added2.66 ml of tert-butyllithium (1.55 M in hexanes, 4.14 mmol) via syringeover 5 minutes. The reaction was stirred at −78° C. for 30 minutes. Asolution of 0.5 g (1.65 mmol) compound from Example 1, step B in 1.65 mldiethyl ether was added. This reaction mixture was stirred at −78° C.for 30 minutes followed by 1.5 h at 0° C. The crude reaction wasfiltered over a pad of silica gel with excess diethyl ether, which wassubsequently removed in vacuo. The product obtained is approximately a1.2:1 ratio of diastereomers at the newly formed secondary alcohol. Thediastereomers were readily separated by chromatography on silica gel (4to 8% ethyl acetate/hexanes gradient). Yield: 40% (desireddiastereomer), 58% (undesired diastereomer).

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.17 (d, J=8.34 Hz, 1H), 7.07-7.11(m, 1H), 7.03 (d, J=1.77 Hz, 1H), 6.85 (d, J=8.59 Hz, 2H), 6.56 (d,J=8.34 Hz, 2H), 5.80 (d, J=3.79 Hz, 1H), 4.70 (d, J=4.80 Hz, 1H), 4.20(d, J=3.79 Hz, 1H), 4.07 (dd, J=4.80, 3.03 Hz, 1H), 3.97 (d, J=3.03 Hz,1H), 3.85 (d, J=3.03 Hz, 2H), 3.16 (br. s., 1H), 1.27 (s, 3H), 1.13 (s,3H), 0.80 (s, 9H), 0.73 (s, 9H), 0.00 (s, 6H), −0.06 (s, 3H), −0.18 (s,3H).

C. Preparation of(2S,3R,4R,5S)-2-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol.Acetyl chloride (0.17 ml) was added to 7 ml of methanol and stirred for15 minutes at room temperature. This solution was transferred to a vialcharged with 0.446 g compound from step B, which was then sealed andheated to 80° C. for 1 h. The reaction was cooled to ambient temperatureand quenched with 50 ml saturated aqueous sodium bicarbonate. Thisaqueous layer was extracted with ethyl acetate (3×50 ml). The combinedorganic layers were washed with brine, dried over magnesium sulfate, andthe solvent was removed in vacuo. The residue was purified by silica gelchromatography (0 to 20% methanol/dichloromethane gradient) to provideapproximately a 1:1 mixture of α:β anomers. Yield: 65%.

¹H NMR (400 MHz, Acetone) δ ppm 8.12 (br. s., 1H), 7.33-7.40 (m, 2H),7.29 (dd, J=8.08, 1.77 Hz, 1H), 7.06 (d, J=8.34 Hz, 3H), 6.75 (d, J=8.34Hz, 2H), 4.73 (d, J=3.54 Hz, 0.5Hα), 4.41 (d, J=9.60 Hz, 0.5Hα), 4.33(d, J=7.58 Hz, 0.5Hβ), 4.19 (d, J=9.35 Hz, 0.5Hβ), 4.01 (t, J=3.28 Hz,2H), 3.72 (t, J=9.09 Hz, 0.5H), 3.44-3.55 (m, 1H), 3.41 (s, 1.5Hβ), 3.35(s, 1.5Hα), 3.27-3.37 (m, 1.5H). MS (ES+) [M+NH₄]⁺=398.

6.11. Example 11 Synthesis of(2S,3R,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol

Toluene-4-sulfonic acid (S)-(tetrahydro-furan-3-yl) ester (31 mg, 0.126mmol) was added to a suspension of compound from Example 10, step C (16mg, 0.042 mmol) and cesium carbonate (46 mg, 0.126 mmol) in 0.22 mlN,N-dimethylformamide. The reaction vessel was sealed and heated to 80°C. for 15 h. Upon cooling to room temperature, the crude reactionmixture was quenched with 2 ml brine and extracted with ethyl acetate(3×2 ml). The combined organic extracts were dried over sodium sulfateand concentrated in vacuo. Chromatography on silica gel (0 to 10%methanol/dichloromethane gradient) provided(2S,3R,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triolas a clear, viscous oil, which upon concentration in dichloromethane wasobtained as a white solid (10 mg, 55% yield).

¹H NMR (400 MHz, Acetone) δ ppm 7.35-7.41 (m, 2H), 7.30 (dd, J=8.34,2.02 Hz, 1H), 7.16 (d, J=7.58 Hz, 2H), 6.83 (d, J=8.59 Hz, 2H),4.93-5.01 (m, 1H), 4.74 (d, J=3.79 Hz, 0.5Hα), 4.42 (d, J=9.60 Hz,0.5Hα), 4.33 (d, J=7.58 Hz, 0.5Hβ), 4.20 (d, J=9.60 Hz, 0.5Hβ), 4.05 (t,J=2.53 Hz, 2H), 4.05 (d, J=5.31 Hz, 2H), 3.93 (dd, J=10.11, 4.80 Hz,1H), 3.75-3.89 (m, 2H), 3.72 (t, J=9.09 Hz, 1H), 3.50 (t, J=9.09 Hz,1H), 3.41 (s, 1.5Hβ), 3.35 (s, 1.5Hα), 3.29-3.34 (m, 3H), 2.16-2.27 (m,1H), 1.97-2.04 (m, 1H). MS (ES+) [M+NH4]+=468.

6.12. Example 12 Synthesis of(2S,3S,4S,5R)-2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-piperidine-3,4,5-triol

A. Preparation of((3aS,5S,6R,6aS)-5-{azido-[(S)-4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methyl}-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yloxy)-tert-butyl-dimethyl-silane.To a solution of the C5 epimer of alcohol from Example 1, step D (682mg, 1.24 mmol) and PPh₃ (489 mg, 1.87 mmol) in THF (6.2 ml) was addedDIAD (366 μl, 1.87 mmol) followed by diphenyl phosphoryl azide (DPPA,323 μl, 1.49 mmol). The reaction was stirred for 1.5 hours, quenchedwith sat. aq. NH₄Cl, diluted with Et₂O, washed with H₂O and brine (withback extraction), dried over MgSO₄, and concentrated under vacuum. Theresidue was purified by flash chromatography (40 g SiO₂, 0-8%EtOAc:Hex.) to give((3aS,5S,6R,6aS)-5-{azido-[(S)-4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methyl}-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yloxy)-tert-butyl-dimethyl-silane(636 mg, 1.11 mmol, 89%) as a yellow oil.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.40 (d, J=8.08 Hz, 1H), 7.16-7.20(m, 1H), 7.15 (d, J=2.02 Hz, 1H), 7.10 (d, J=8.59 Hz, 2H), 6.80-6.85 (m,2H), 5.79 (d, J=3.54 Hz, 1H), 4.58 (d, J=9.85 Hz, 1H), 4.36 (d, J=3.54Hz, 1H), 4.30 (d, J=2.53 Hz, 1H), 4.14 (dd, J=9.98, 2.65 Hz, 1H),3.98-4.10 (m, 4H), 1.38-1.43 (m, 6H), 1.29 (s, 3H), 0.96 (s, 9H), 0.20(s, 6H); MS (ES+) [M+NH₄]⁺=591.

B. Preparation of(2R,3S,4S,5S)-5-{azido-[(S)-4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methyl}-tetrahydro-furan-2,3,4-triol.Acetyl chloride (0.175 ml, 2.45 mmol) was added to MeOH (7 ml). Thesolution was stirred 15 minutes, then added to azide from step A (392mg, 0.68 mmol). The reaction was stirred for 16 hours, then concentratedunder vacuum, rotovapped 2 times with MeOH, and placed on the highvacuum to give a white solid. The solid was treated with 1:1 AcOH:H₂O (7ml) at 100° C. for 2.5 hours. The reaction was concentrated undervacuum, rotovapped 2 times with toluene, and placed on the high vacuum.The residue was purified by flash chromatography (40 g SiO₂, 0-6%MeOH:CH₂Cl₂) to give(2R,3S,4S,5S)-5-{azido-[(S)-4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methyl}-tetrahydro-furan-2,3,4-triol(223 mg, 0.53 mmol, 78%) as a mixture of anomers.

¹H NMR (400 MHz, MeOD) δ ppm 7.39 (dd, J=8.46, 3.41 Hz, 1H), 7.24-7.30(m, 2H), 7.09 (d, J=8.84 Hz, 2H), 6.81 (dd, J=8.59, 1.77 Hz, 2H), 5.33(d, J=3.54 Hz, 0.5H), 4.98 (s, 0.5H), 4.84 (d, J=10.17 Hz, 0.5H), 4.66(d, J=9.09 Hz, 0.5H), 4.10-4.23 (m, 2H), 3.97-4.05 (m, 4.5H), 3.89 (dd,J=3.66, 1.89 Hz, 0.5H), 1.36 (t, J=6.95 Hz, 3H); MS (ES+) [M+NH₄]⁺=437.

C. Preparation of(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-piperidine-3,4,5-triol.Compound from step B (216 mg, 0.52 mmol) was hydrogenated underatmospheric pressure H₂ over PtO₂ (6 mg, 0.026 mmol) in MeOH (5 ml) withAcOH (0.25 ml) for 6 hours. The reaction was filtered, concentratedunder vacuum, diluted with EtOAc, washed with 10% aq. K₂CO₃ and brine,dried over Na₂SO₄, filtered, and concentrated under vacuum. A portion ofthe material (about 55 mg) was purified prep HPLC (Sunfire C18 30×100 mmcolumn, 20-70% MeCN:H₂O (10 mM NH₄OAc), 15 minutes, 45 ml/min) andlyophilized to give(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-piperidine-3,4,5-triol(27 mg, 0.071 mmol) as a white solid.

¹H NMR (400 MHz, MeOD) δ ppm 7.35 (d, J=8.08 Hz, 1H), 7.29 (d, J=2.02Hz, 1H), 7.21-7.25 (m, 1H), 7.10 (d, J=8.34 Hz, 2H), 6.79 (d, J=8.59 Hz,2H), 4.02 (s, 2H), 3.99 (q, J=7.07 Hz, 2H), 3.57 (ddd, J=10.55, 8.65,5.05 Hz, 1H), 3.33-3.40 (m, 2H), 3.25-3.29 (m, 1H), 3.12 (dd, J=12.00,5.18 Hz, 1H), 2.56 (dd, J=11.87, 10.86 Hz, 1H), 1.35 (t, J=6.95 Hz, 3H);MS (ES+) [M+H]⁺=378.

6.13. Example 13 Synthesis of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfinyl-tetrahydro-pyran-3,4,5-trioland(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol

A. Preparation of(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethylsulfanyl-tetrahydro-pyran-3,4,5-triol.To a solution of bromide from Example 5, step B (291 mg, 0.50 mmol) inEtOH (5 ml) at 0° C. was added NaSEt (84 mg, 1.0 mmol). The reaction wasstirred 30 minutes, then diluted with EtOAc, washed with dilute aq. NaOHand with brine (with back extraction), dried over Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by flashchromatography (40 g SiO₂, 0-7% MeOH:CH₂Cl₂), suspended in H₂O, andlyophilized to give(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethylsulfanyl-tetrahydro-pyran-3,4,5-triol(126 mg, 0.29 mmol, 58%) as a white powder.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.08 Hz, 1H), 7.18-7.26(m, 2H), 7.10 (d, J=8.59 Hz, 2H), 6.80-6.85 (m, 2H), 4.46 (d, J=9.60 Hz,1H), 4.17 (d, J=9.35 Hz, 1H), 3.98-4.11 (m, 4H), 3.67-3.73 (m, 1H),3.49-3.57 (m, 2H), 2.79 (d, J=2.27 Hz, 1H), 2.67-2.77 (m, 2H), 2.53 (d,J=1.77 Hz, 1H), 2.04 (d, J=2.78 Hz, 1H), 1.41 (t, J=6.95 Hz, 3H), 1.29(t, J=7.45 Hz, 3H); MS (ES+) [M+NH₄]⁺=456.

B. Preparation of(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-trioland(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol.To a solution of compound from step A (10 mg, 0.023 mmol) in AcOH (0.5ml) was added H₂O₂ (35 wt % solution in H₂O, 3 mg, 0.092 mmol, 9 μl).The mixture was stirred at ambient temperature for 2 hours before beingconcentrated under vacuum. Purification of the mixture by silica gelchromatography (5% MeOH/CH₂Cl₂) afforded(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfinyl-tetrahydro-pyran-3,4,5-triol(as a mixture of diastereomers at sulfur) (2 mg, 19%) and(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol(5 mg, 46%) both as white solids.

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfinyl-tetrahydro-pyran-3,4,5-triol:¹H NMR (400 MHz, methanol) δ ppm 7.37 (m, 3H), 7.31 (m, 1H), 7.24 (m,2H), 7.10 (m, 4H) 6.81 (m, 4H), 4.46 (d, J=9.9 Hz, 1H), 4.28 (d, J=9.6Hz, 1H), 4.25 (d, J=9.6 Hz, 1H), 4.19 (d, J=9.9 Hz, 1H), 4.03 (m, 4H),4.00 (m, 4H), 3.85 (t, J=9.6 Hz, 1H), 3.76 (t, J=9.6 Hz, 1H), 3.57 (m,2H), 3.37 (m, 2H), 3.09 (m, 1H), 2.99 (m, 1H), 2.91 (m, 1H), 2.80 (m,1H), 1.31 (m, 12H); MS (ES+) [M+H]⁺=455.

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol:¹H NMR (400 MHz, methanol) δ ppm 7.28 (m, 1H), 7.16 (m, 2H), 6.99 (d,J=8.6 Hz, 2H), 6.71 (d, J=8.6 Hz, 2H), 4.46 (d, J=9.6 Hz, 1H), 4.19 (d,J=9.4 Hz, 1H), 3.90 (m, 4H), 3.81 (t, J=9.3 Hz, 1H), 3.46 (t, J=9.1 Hz,1H), 3.24 (t, J=9.1 Hz, 1H), 2.98 (m, 2H), 1.26 (t, J=6.8 Hz, 3H), 1.18(t, J=7.6 Hz, 3H); MS (ES+) [M+NH₄]⁺=488.

6.14. Example 14 Synthesis of Acetic acid(2R,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4ethoxy-benzyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-yl ester

A. Preparation of(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol.To a solution of bromide from Example 5, step B (347 mg, 0.60 mmol.) inEtOH (6 ml) at 0° C. was added NaSMe (70 mg, 0.72 mmol.). The reactionwas stirred 30 minutes, then diluted with EtOAc, washed with dilute aq.NaOH and with brine (with back extraction), dried over Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by flashchromatography (40 g SiO₂, 0-7% MeOH:CH₂Cl₂), suspended in H₂O, andlyophilized to give(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol(212 mg, 0.43 mmol., 72%) as a white powder.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (d, J=8.34 Hz, 1H), 7.22 (dd,J=8.08, 2.27 Hz, 1H), 7.17 (d, J=2.02 Hz, 1H), 7.10 (d, J=8.59 Hz, 2H),6.83 (d, J=8.84 Hz, 2H), 4.38 (d, J=9.60 Hz, 1H), 4.19 (d, J=9.35 Hz,1H), 3.98-4.11 (m, 4H), 3.67-3.73 (m, 1H), 3.48-3.59 (m, 2H), 2.80 (d,J=2.27 Hz, 1H), 2.53 (d, J=2.02 Hz, 1H), 2.19 (s, 3H), 2.04 (d, J=2.78Hz, 1H), 1.41 (t, J=6.95 Hz, 3H); MS (ES+) [M+NH₄]⁺=442.

B. Preparation of acetic acid(2R,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-ylester. Triol from step A (45 mg, 0.11 mmol.) was treated with aceticanhydride (60 μl, 0.64 mmol.) in pyridine (0.5 ml) for 16 hours. Thereaction was diluted with Et₂O, washed with 1 M aq. NaHSO₄, H₂O, sat.aq. NaHCO₃, and brine (with back extraction), dried over MgSO₄,filtered, and concentrated under vacuum. The residue was purified byflash chromatography (4 g SiO₂, 0-25% EtOAc/Hex), suspended in H₂O, andlyophilized to acetic acid(2R,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-ylester (46 mg, 0.087 mmol., 79%) as a white solid.

¹H NMR (400 MHz, Chloroform-d) δ ppm 7.36 (d, J=8.08 Hz, 1H), 7.18 (dd,J=8.21, 2.15 Hz, 1H), 7.02-7.10 (m, 3H), 6.83 (d, J=8.59 Hz, 2H),5.27-5.34 (m, 1H), 5.19 (t, J=9.60 Hz, 1H), 5.04 (t, J=9.60 Hz, 1H),4.50 (d, J=9.85 Hz, 1H), 4.37 (d, J=9.85 Hz, 1H), 3.95-4.08 (m, 4H),2.16 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.72 (s, 3H), 1.41 (t, J=7.07Hz, 3H); MS (ES+) [M+NH₄]⁺=568.

6.15. Example 15 Synthesis of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol

To a solution of the compound from Example 14, step A (41 mg, 0.097mmol) in AcOH (0.5 ml) was added H₂O₂ (35 wt % solution in H₂O, 20 mg,0.58 mmol, 57 μl). The mixture was stirred at ambient temperature for 18hours before being concentrated under vacuum. Purification of themixture by silica gel chromatography (5% MeOH/CH₂Cl₂) afforded(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol(20 mg, 45%) as a white solid.

¹H NMR (400 MHz, methanol) δ ppm 7.28 (m, 1H), 7.27 (m, 2H), 7.10 (d,J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.53 (d, J=9.6 Hz, 1H), 4.30 (d,J=9.6 Hz, 1H), 4.00 (m, 4H), 3.88 (t, J=9.1 Hz, 1H), 3.55 (t, J=9.1 Hz,1H), 3.35 (t, J=9.1 Hz, 1H), 2.92 (s, 3H), 1.36 (t, J=6.8 Hz, 3H); MS(ES+) [M+NH₄]⁺=474.

6.16. Example 16 Synthesis of1-{(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidin-1-yl}-ethanone

Preparation of1-{(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidin-1-yl}-ethanone.To a solution of the crude compound from Example 12, step C (38 mg, 0.1mmol.) in MeOH (1 mL) was added acetic anhydride (19 μL, 0.2 mmol.). Thereaction was stirred for 4 hours, more acetic anhydride (10 μL, 0.1mmol) was added, and stirring was continued overnight. The reaction wasdiluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, dried overNa₂SO₄, filtered, and concentrated under vacuum. The residue waspurified by flash chromatography (12 g SiO₂, 0-8% MeOH:CH₂Cl₂),suspended in H₂O, and lyophilized to give1-{(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidin-1-yl}-ethanone(14 mg, 0.033 mmol., 33% for 2 steps) as a white solid.

¹H NMR (400 MHz, MeOD) δ ppm 7.33 (d, J=8.34 Hz, 1H), 7.18 (dd, J=8.46,2.15 Hz, 1H), 7.11 (d, J=1.77 Hz, 1H), 7.07 (d, J=8.84 Hz, 2H), 6.81 (d,J=8.84 Hz, 2H), 3.96-4.03 (m, 4H), 3.83-3.89 (m, 1H), 3.73-3.77 (m, 1H),3.55-3.59 (m, 1H), 2.09 (br. s., 3H), 1.36 (t, J=6.95 Hz, 3H); MS (ES+)[M+H]⁺=420.

6.17. Example 17 Synthesis of(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidine-1-carboxylicacid methyl ester

To a solution of the crude compound from Example 12, step C (38 mg, 0.1mmol.) and NaHCO₃ (42 mg, 0.5 mmol.) in 1:1:1 EtOAc:EtOH:H₂O (1.5 mL) at0° C. was added methyl chloroformate (23 μL, 0.3 mmol.). The reactionwas stirred for 1 hour, then diluted with EtOAc, washed with H₂O andbrine (with back extraction), dried over Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by flashchromatography (4 g SiO₂, 0-10% MeOH:CH₂Cl₂, suspended in H₂O, andlyophilized to give(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidine-1-carboxylicacid methyl ester (12 mg, 0.026 mmol., 26% for 2 steps) as a whitesolid.

¹H NMR (400 MHz, MeOD) δ ppm 7.32 (d, J=8.34 Hz, 1H), 7.15 (dd, J=8.34,2.02 Hz, 1H), 7.10 (d, J=2.27 Hz, 1H), 7.04-7.09 (m, 2H), 6.81 (d,J=8.59 Hz, 2H), 4.80 (d, J=6.06 Hz, 1H), 4.00 (q, J=7.07 Hz, 5H),3.81-3.86 (m, 1H), 3.70-3.73 (m, 1H), 3.60 (s, 3H), 3.54-3.59 (m, 1H),3.46 (dd, J=14.40, 3.28 Hz, 1H), 1.36 (t, J=6.95 Hz, 3H); MS (ES+)[M+H]⁺=436.

6.18. Example 18 Synthesis of(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidine-1-carboxylicacid allyl amide

To a solution of the crude compound from Example 12, step C (38 mg, 0.1mmol.) in 1:1 EtOH:EtOAc (1 mL) was added allyl isocyanate (18 μL, 0.2mmol.). The reaction was stirred for 1 hour, then concentrated undervacuum. The residue was purified by flash chromatography (4 g SiO₂,0-10% MeOH:CH₂Cl₂, suspended in H₂O, and lyophilized to give(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-piperidine-1-carboxylicacid allyl amide (14 mg, 0.030 mmol., 30% for 2 steps) as a white solid.

¹H NMR (400 MHz, MeOD) δ ppm 7.32 (d, J=8.1 Hz, 1H), 7.16-7.20 (m, 2H),7.07 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 5.68-5.79 (m, J=17.2,10.2, 5.3, 5.2 Hz, 1H), 4.92-5.00 (m, 2H), 4.77 (d, J=6.3 Hz, 1H),3.94-4.05 (m, 4H), 3.86 (dd, J=14.0, 3.4 Hz, 1H), 3.69-3.81 (m, 3H),3.59-3.68 (m, 1H), 3.56 (dd, J=7.3, 5.1 Hz, 1H), 3.47 (dd, J=13.9, 3.5Hz, 1H), 1.36 (t, J=6.9 Hz, 3H); MS (ES+) [M+H]⁺=461.

6.19. Example 19 Synthesis of(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-piperidine-3,4,5-triol

To a solution of the compound from Example 12, step C (50 mg, 0.13mmol.) and K₂CO₃ (55 mg, 0.40 mmol.) in DMF (0.65 mL) was added methyliodide (10 μL, 0.16 mmol.). The reaction was stirred for 3 hours, thendiluted with EtOAc, washed with H₂O and brine (with back extraction),dried over Na₂SO₄, filtered, and concentrated under vacuum. The residuewas purified by flash chromatography (12 g SiO₂, 2-12% MeOH:CH₂Cl₂),suspended in H₂O, and lyophilized to give(2S,3S,4S,5R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-piperidine-3,4,5-triol(16 mg, 0.040 mmol., 31%) as a white solid.

¹H NMR (400 MHz, MeOD) δ ppm 7.35 (d, J=8.1 Hz, 1H), 7.20-7.24 (m, 1H),7.17 (dd, J=8.2, 1.9 Hz, 1H), 7.09 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz,2H), 4.03 (s, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.64 (ddd, J=10.5, 9.2, 4.8Hz, 1H), 3.33-3.37 (m, 1H), 3.21 (t, J=9.0 Hz, 1H), 3.03 (dd, J=11.1,4.8 Hz, 1H), 2.74 (d, J=9.3 Hz, 1H), 2.15 (t, J=10.9 Hz, 1H), 1.95 (s,3H), 1.36 (t, J=6.9 Hz, 3H); MS (ES+) [M+H]⁺=392.

6.20. Example 20 Synthesis of(2S,3S,4R,5R,6R)-2-[3-(4-Ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol

A. Preparation of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyron-2-one.Tetra-O-benzyl-D-glucopyranose (2.07 g, 3.8 mmol) was dissolved in DMSO(10.1 mL). To this mixture was added acetic anhydride (7.0 mL) andstirred at room temperature overnight. To the reaction mixture ice wasadded and stirred for 1 h. The mixture was extracted with ether (3×20mL). The extract was washed with water (2×10 mL), aqueous sodiumbicarbonate (2×10 mL), brine, dried (sodium sulfate) and concentratedunder vacuo. Flash silica gel column chromatography with 0-25%ethylacetate/Hexane resulted in 1.712 g of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyron-2-one(83%).

B. Preparation of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2-ol.n-Butyl lithium (2.5N in hexane) (1.263 mL, 3.16 mmol) was addeddropwise to a solution of compound from Example 1, step C (1.028 g, 3.16mmol) in anhydrous THF (15 mL) at −78° C. After stirring for 30 min at−78° C., a solution of compound from step A (1.7 g, 3.16 mmol) inanhydrous THF (10 mL) was added dropwise and stirred for 1 h whileallowing to warm to room temperature. Aqueous ammonium chloride (10 mL)was added to the reaction mixture, THF removed under vacuum, and aqueouslayer extracted with ethyl acetate (2×20 mL). Combined organic phaseswashed with brine, dried (sodium sulfate) and concentrated under vacuum.Crude mixture purified by flash silica gel column chromatography with0-20% ethyl acetate/Hexane to give 712 mg of(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2-ol(29%). M+H₂O=802.1

C. Preparation of(2R,3R,4S)-2,3,4,6-tetrakis(benzyloxy)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexane-1,5-dione.To a stirred solution of Dess-Martin reagent (500 mg, excess) in CH₂Cl₂(10 mL) was added compound from step B (500 mg, 0.6 mmol)) in anhydrousdichloromethane (10 mL) and stirred overnight. Reaction mixture quenchedwith 1N sodium hydroxide (3 mL), extracted with dichloromethane (2×10mL), combined organic fractions were washed with brine, dried oversodium sulfate, concentrated under reduced pressure to get crude product487 mg. (M+H₂O=800.1)

D. Preparation of(3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)piperidine.A solution of compound from step C (400 mg, 0.5 mmol), 7N ammonia inMeOH (1.0 mL) and freshly activated 4 Å molecular sieves (250 mg) indichloromethane (20 mL) were refluxed overnight. The reaction mixturewas cooled to room temperature, then sodium cyanoborohydride (160 mg,2.55 mmol) was added and refluxed for additional 2 h. The reactionmixture was filtered, diluted with dichloromethane (20 mL), washed withwater, brine, dried (sodium sulfate), and concentrated under reducedpressure. Chromatography on silica gel (50 to 100% acetonitrilecontaining 0.1% ammonium acetate/water gradient) provided(3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)piperidine(136 mg, 34%).

¹H NMR (400 MHz, Chloroform-d) δ ppm 1.41 (t, J=7.07 Hz, 3H) 2.98 (ddd,J=9.40, 8.50, 2.53 Hz, 1H) 3.40 (t, J=9.22 Hz, 1H) 3.41 (t, J=8.59 Hz,1H) 3.43 (t, J=9.09 Hz, 1H) 3.56 (d, J=9.35 Hz, 1H) 3.68 (t, J=8.84 Hz,1H) 3.79 (dd, J=8.97, 2.65 Hz, 1H) 3.84 (d, J=10.36 Hz, 1H) 3.97 (d,J=13.60 Hz, 1H) 3.99 (q, J=7.07 Hz, 2H) 4.10 (d, J=15.30 Hz, 1H) 4.43(d, J=10.36 Hz, 1H) 4.48 (d, J=2.53 Hz, 2H) 4.56 (d, J=10.86 Hz, 1H)4.88 (d, J=10.86 Hz, 1H) 4.89 (d, J=11.12 Hz, 1H) 4.93 (d, J=10.86 Hz,1H) 6.77 (d, J=8.59 Hz, 2H) 6.88 (dd, J=7.71, 1.64 Hz, 2H) 7.07 (d,J=8.59 Hz, 2H) 7.16-7.38 (m, 21H); MS (ES+) [M+H]⁺=768.2.

E. Preparation of(3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methylpiperidine.Compound from step D (50 mg, 0.065 mmol) was dissolved in acetonitrile(1 mL) and treated with potassium carbonate (18 mg, 0.13 mmol) for 30minutes To this mixture iodomethane (20 uL, 0.32 mmol) was added andstirred overnight. The reaction mixture was diluted with ethyl acetate(10 mL), washed with water, brine, dried (sodium sulfate), andconcentrated under vacuum. Chromatography on silica gel (50 to 100%acetonitrile containing 0.1% ammonium acetate/water gradient) provided(3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methylpiperidine(29 mg, 56%). MH+ 782.1.

F. Preparation of(2S,3S,4R,5R,6R)-2-[3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol.Compound from step E (50 mg) in methanol and acetic acid (25 uL) wastreated 5% wet Pd—C (10 mg) under H₂ atmosphere for 4 h. The reactionmixture was filtered through a pad of celite and concentrated.Chromatography on silica gel (10 to 100% acetonitrile containing 0.1%ammonium acetate/water gradient) provided(2S,3S,4R,5R,6R)-2-[3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol(6 mg, 70%).

¹H NMR (400 MHz, Chloroform-d) δ ppm 1.40 (t, J=6.95 Hz, 3H) 2.02 (s,3H) 2.05 (br. s., 3H) 2.15 (d, J=8.84 Hz, 1H) 3.01 (d, J=4.55 Hz, 2H)3.50 (d, J=5.05 Hz, 2H) 3.77 (br. s., 2H) 3.85 (d, J=8.59 Hz, 2H) 3.91(br. s., 2H) 3.99 (q, J=7.24 Hz, 2H) 6.81 (d, J=8.59 Hz, 2H) 7.06 (d,J=8.59 Hz, 2H) 7.09 (br. s., 1H) 7.18 (br. s., 2H) 7.24 (d, J=7.58 Hz,1H); MS (ES+) [M+H]⁺=387.0.

6.21. Example 21 Synthesis of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-thiopyran-3,4,5-triol

A. Preparation of(S-(1S)-((3aS,6S,6aS)-6-(tert-butyldimethylsilyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(4-chloro-3-(4-ethoxybenzyl)phenyl)methylbenzothioate. Diethylazodicarboxylate (150 μL, 0.914 mmol) was added toa solution of triphenylphosphine (240 mg, 0.914 mmol) in 1.0 mL of THFat room temperature. After one hour, the C5 epimer from Example 1, stepD (167 mg, 0.305 mmol) was added in 0.5 mL THF via syringe and wasfollowed by the addition of thiobenzoic acid (110 μL, 0.914 mmol) viasyringe. This orange solution was stirred for 22 hours at roomtemperature. After removal of solvents in vacuo, the residue waspurified by flash chromatography (0 to 10% ethyl acetate/hexanesgradient) to provide the title compound as a light yellow oil (104 mg,50% yield). MS (ES+) [M+NH₄]⁺=566.

B. Preparation of(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-thiopyran-3,4,5-triol.Sodium methoxide (0.3 mL of a 4.3M solution in methanol) was added to asolution of the compound from Step A (104 mg, 0.152 mmol) in 6 mLmethanol. After 30 minutes, the reaction was diluted with 20 mL ethylacetate and washed with water and brine (20 mL each). The organic layerwas dried with magnesium sulfate, filtered and solvents removed invacuo. The residue was purified quickly by flash chromatography (5%ethyl acetate/hexanes) and the product was carried on directly toprevent disulfide formation.

One drop of acetyl chloride was added to 1 mL of methanol and stirredfor 15 minutes at room temperature. This acidic solution was added tothe free thiol from above and heated for 42 hours at 80° C. The reactionwas cooled to room temperature and the solvent was removed in vacuo. Thecrude residue was purified by prep HPLC (30×250 mm C18 column, 5-75%acetonitrile:water (10 mM ammonium acetate), 15 minutes, 45 mL/min) toafford the title compound (alpha anomer, t=13.82 minutes, 8.7 mg, 13%yield for 2 steps).

¹H NMR (400 MHz, acetone-d₆) δ ppm 7.33 (m, 2H), 7.25 (dd, J=2.27, 8.34Hz, 1H), 7.13 (d, J=8.59 Hz, 2H), 6.82 (d, J=8.59 Hz, 2H), 4.48 (d,J=3.03 Hz, 1H), 4.02 (s, 2H), 3.99 (q, J=7.07 Hz, 2H), 3.91 (d, J=10.36Hz, 1H), 3.80-3.85 (m, 2H), 3.68 (dd, J=8.37, 9.35 Hz, 1H), 3.42 (s,3H), 1.33 (t, J=7.07 Hz, 3H). MS (ES+) [M+NH₄]⁺=424.

6.22. Example 22 Synthesis of(2S,3S,4R,5R,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-piperidine-3,4,5-triol

A. Preparation of(2R,3R,4S,5R,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-methoxy-tetrahydro-pyran.To a solution of α-D-methylglucoside (3 g, 15.45 mmol) in DMF (50 ml)was added NaH (60% dispersion in mineral oil, 3.34 g, 0.14 mol). Duringthis addition, a thick suspension forms and an additional amount of DMF(15 ml) was added to get back into solution. After stirring at roomtemperature for 30 minutes, the mixture was cooled to 0° C. and allylbromide (17 g, 0.14 mol, 12 ml) was added slowly. The mixture was thenallowed to warm to room temperature and stirred for 18 hours. MeOH wascarefully added to the light brown mixture to quench excess NaH and thenthe mixture was concentrated. The residue was diluted with CH₂Cl₂ andwashed with H₂O, dried (MgSO₄) and concentrated to afford a yellow oil.Purification by silica gel chromatography (20% EtOAc/hexanes) afforded(2R,3R,4S,5R,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-methoxy-tetrahydro-pyran(4.06 g, 11.47 mmol, 74%) as a colorless oil. TLC: R_(f)=0.20, 20%EtOAc/hexanes.

B. Preparation of(3R,4S,5R,6R)-3,4,5-tris-allyloxy-6-allyloxymethyl-tetrahydro-pyran-2-ol.A solution of compound from Step A (10 g, 0.028 mol) in AcOH (400 ml)was warmed to 90° C. TfOH (2 N solution in H₂O, 16.69 g, 0.112 mol, 56ml) was added and the mixture stirred at 90° C. for 75 minutes. Thesolution was cooled and diluted with CH₂Cl₂, washed with H₂O (×3),NaHCO₃ sat., dried (MgSO₄) and concentrated to give a yellow solid.Purification by silica gel chromatography (20%-40% EtOAc/hexanes)afforded(3R,4S,5R,6R)-3,4,5-tris-allyloxy-6-allyloxymethyl-tetrahydro-pyran-2-olas a mixture of anomers (5.85 g, 17.2 mmol, 61%) as a white solid. TLC:R_(f)=0.40, 40% EtOAc/hexanes.

C. Preparation of(3R,4S,5R,6R)-3,4,5-tris-allyloxy-6-allyloxymethyl-tetrahydro-pyran-2-one.Oxalyl chloride (2.75 g, 21.7 mmol, 1.89 ml) was dissolved in CH₂Cl₂ (90ml) and the mixture cooled to −78° C. DMSO (3.39 g, 43.4 mmol, 3.08 ml)was added as a solution in CH₂Cl₂ (60 ml). The mixture was stirred at−78° C. for 15 minutes and then compound from Step B (6.70 g, 19.7 mmol)was added as a solution in CH₂Cl₂ (150 ml). The reaction mixture wasstirred for a further 15 minutes at −78° C. and Et₃N (9.97 g, 98.5 mmol,13.7 ml) added. The mixture was stirred at −78° C. for a further 5minutes and then allowed to warm to room temperature over 30 minutes.The reaction was quenched with H₂O and the organic layer separated,washed twice with H₂O, dried and concentrated to give a pale yellow oil.Purification by silica gel chromatography (15% EtOAc/hexanes) afforded(3R,4S,5R,6R)-3,4,5-tris-allyloxy-6-allyloxymethyl-tetrahydro-pyran-2-one(2.49 g, 7.37 mmol, 37%) as a colorless oil. TLC: R_(f)=0.40, 20%EtOAc/hexanes.

D. Preparation of(3R,4S,5R,6R)-3,4,5-tris-allyloxy-6-allyloxymethyl-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-ol.Compound from Example 1, Step C (2.37 g, 7.31 mmol) was dissolved in THF(25 ml) and cooled to −78° C. n-BuLi (2.5 N solution in hexanes, 0.47 g,7.31 mmol, 2.92 ml) was added dropwise and the solution stirred for 15minutes. Compound from Step C (2.47 g, 7.31 mmol) was added as asolution in THF (25 ml) and the reaction mixture stirred at −78° C. fora further 15 minutes before being allowed to warm to room temperatureover 30 minutes. The reaction was quenched with NH₄Cl sat. and theorganic layer separated. The aqueous layer was back extracted with Et₂Oand the combined organics dried and concentrated to give a yellow oil.Purification by silica gel chromatography (10%-20% EtOAc/hexanes)afforded(3R,4S,5R,6R)-3,4,5-tris-allyloxy-6-allyloxymethyl-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-ol(0.95 g, 1.63 mmol, 22%) as a colorless oil. MS (ES+) [M+NH₄]⁺=602.

E. Preparation of(2R,3R,4S)-2,3,4,6-tetrakis-allyloxy-1-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-hexane-1,5-dione.To a solution of compound from Step D (0.93 g, 1.59 mmol) in CH₂Cl₂ (25ml) was added Dess-Martin periodinane (0.68 g, 1.59 mmol). The mixturewas stirred at room temperature for 1 hour and then a second portion ofDess-Martin periodinane (1 eqiv.) was added. Stirring was continued foranother hour and then the reaction was quenched with 1N NaOH (˜4 ml).H₂O was added and the organic layer separated. The aqueous layer wasback extracted with CH₂Cl₂, dried and concentrated to give a yellow waxysolid. Purification by silica gel chromatography (15%-20% EtOAc/hexanes)afforded(2R,3R,4S)-2,3,4,6-tetrakis-allyloxy-1-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-hexane-1,5-dione(0.60 g, 1.03 mmol, 65%) as a white solid. MS (ES+) [M+NH₄]⁺=600.

F. Preparation of(2R,3R,4R,5S,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-piperidine.To a solution of compound from Step E (0.60 g, 1.03 mmol) in MeOH (12ml) was added 4 Å MS followed by ammonium formate (0.13 g, 2.06 mmol).NaBH₃CN (0.14 g, 2.3 mmol) was then added in one portion and the mixturestirred at room temperature for 1 hour 30 minutes. The reaction mixturewas then filtered and concentrated. Purification by silica gelchromatography (10%-20% EtOAc/hexanes) afforded(2R,3R,4R,5S,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-piperidine(155 mg, 0.27 mmol, 27%). MS (ES+) [M+H]⁺=568.

G. Preparation of(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-tris-[((E)-propenyl)oxy]-6-[((E)-prop enyl)oxymethyl]-piperidine. Ir(COD)[PCH₃Ph₂]PF₆(8 mg, 30 mol %) in THF (0.3 ml) was stirred under an atmosphere of H₂until the color changed from red to pale yellow (˜5 minutes). Compoundfrom Step F (19 mg, 0.033 mol) in THF (0.5 ml) was then added and themixture stirred at room temperature for 45 minutes and thenconcentrated. Purification by silica gel chromatography (20%EtOAc/hexanes) afforded(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-tris-[((E)-propenyl)oxy]-6-[((E)-propenyl)oxymethyl]-piperidine(15 mg, 0.026 mmol, 80%) as a colorless oil. MS (ES+) [M+H]⁺=568.

H. Preparation of(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-piperidine-3,4,5-triol.Compound from Step G (15 mg, 0.026 mmol) was dissolved in a solution ofTHF/AcOH/1N HCl (0.2 ml:0.3 ml:0.15 ml) and heated to 70° C. for 30minutes. The mixture was concentrated to give a pale yellow oil.Purification by preparative HPLC (sunfire C18, 30×100 mm, 5 μm, 10%-100%B over 15 minutes) afforded(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-piperidine-3,4,5-triol(5 mg, 0.012 mmol, 46%) as a white solid. MS (ES+) [M+H]⁺=408.

¹H NMR (400 MHz, MeOD) δ ppm 7.36 (m, 2H), 7.28 (m, 1H), 7.12 (d, J=8.6Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 4.05 (m, 2H), 4.00 (q, J=6.8 Hz, 2H),3.92 (dd, J=3.0 Hz and 10.8 Hz, 1H), 3.58 (dd, J=7.6 Hz and 11.1 Hz,1H), 3.47 (m, 1H), 3.26-3.36 (m, 3H), 2.70 (m, 1H), 1.37 (t, J=7.1 Hz,3H).

6.23. Example 23 Synthesis of(2S,3S,4R,5R,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol

A. Preparation of(2R,3R,4R,5S,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-piperidine.To a solution of compound from Example 22, Step F (135 mg, 0.24 mmol) inMeCN was added K₂CO₃ (164 mg, 1.19 mmol). The mixture was stirred for 30minutes and then MeI (676 mg, 4.76 mmol) was added. Stirring wascontinued at room temperature for 8 hours, then the mixture was filteredand concentrated. Purification by silica gel chromatography (10%EtOAc/hexanes) afforded(2R,3R,4R,5S,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-piperidine(90 mg, 0.15 mmol, 65%) as a colorless oil. MS (ES+) [M+H]⁺=582.

B. Preparation of(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-3,4,5-tris-[((E)-propenyl)oxy]-6-[((E)-propenyl)oxymethyl]-piperidine.Ir(COD)[PCH₃Ph₂]PF₆ (27 mg, 30 mol %) in THF (1 ml) was stirred under anatmosphere of H₂ until the color changed from red to pale yellow (˜5minutes). Compound from Step A (62 mg, 0.11 mol) in THF (1.5 ml) wasthen added and the mixture stirred at room temperature for 45 minutesand then concentrated. Purification by silica gel chromatography (20%EtOAc/hexanes) afforded(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-3,4,5-tris-[((E)-propenyl)oxy]-6-[((E)-propenyl)oxymethyl]-piperidine(62 mg, 0.11 mmol, 100%) as a colorless oil. MS (ES+) [M+H]⁺=582.

C. Preparation of(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol.Compound from Step B (54 mg, 0.093 mmol) was dissolved in a solution ofTHF/AcOH/1N HCl (0.5 ml:0.6 ml:0.30 ml) and heated to 70° C. for 30minutes. The mixture was concentrated to give a pale yellow oil.Purification by preparative HPLC (sunfire C18, 30×100 mm, 5 μm, 10%-100%B over 15 minutes) afforded(2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol(22 mg, 0.052 mmol, 56%) as a white solid. MS (ES+) [M+H]⁺=422.

¹H NMR (400 MHz, MeOD) δ ppm 7.31 (m, 2H), 7.22 (m, 1H), 7.07 (d, J=8.8Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4.00 (m, 2H), 3.96 (q, J=7.1 Hz, 2H),3.90 (m, 2H), 3.52 (dd, J=9.4 Hz and 9.4 Hz, 1H), 3.23-3.32 (m, 3H),2.88 (d, J=8.8 Hz, 1H), 2.00 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).

6.24. Additional Compounds

Using the procedures described herein and methods known in the art, theadditional compounds listed below in Table 1 were prepared. Potent SGLT2inhibitors are marked with an asterisk.

TABLE 1 Molecular MS Compound Formula (M + H)⁺(2S,3R,4R,5S)-2-[3-(4-Ethoxy-benzyl)-phenyl]-6- C₂₁H₂₆O₆ 374methoxy-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₇ClO₇ 438.1phenyl]-6-(2-hydroxy-ethoxy)-tetrahydro-pyran-3,4,5- triol*(3S,4R,5R,6S)-2-Benzyloxy-6-[4-chloro-3-(4-ethoxy- C₂₇H₂₉ClO₆ 484.1benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-(4′-Ethoxy-biphenyl-3-yl)-6-methoxy- C₂₀H₂₄O₆ 378tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₂H₂₄ClF₃O₆476.1 6-(2,2,2-trifluoro-ethoxy)-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₃H₂₉ClO₇ 452.16-(2-methoxy-ethoxy)-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₄H₃₂ClNO₆ 466.16-(2-dimethylamino-ethoxy)-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₃H₂₉ClO₅S 4526-propylsulfanyl-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₃H₂₅ClN₂O₅445.1 6-imidazol-1-yl-tetrahydro-pyran-3,4,5-triol{(3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₃H₂₇ClO₈ 466.13,4,5-trihydroxy-tetrahydro-pyran-2-yloxy}-acetic acid methyl ester*(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₆H₃₄ClNO₅ 475.16-(4-methyl-piperidin-1-yl)-tetrahydro-pyran-3,4,5-triol(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₄H₂₇ClN₂O₅S 4916-(5-methyl-thiazol-2-ylamino)-tetrahydro-pyran-3,4,5- triol(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₆H₂₇ClO₆ 470.1phenyl]-6-phenoxy-tetrahydro-pyran-3,4,5-triol*N-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₃H₂₈ClNO₆ 450phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yl}-N- methyl-acetamideAcetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3- C₂₇H₃₁ClO₉ 552(4-ethoxy-benzyl)-phenyl]-2-methoxy-tetrahydro-pyran-3- (M + NH₃)⁺ ylester (2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-phenoxy)- C₂₀H₂₃ClO₇ 428phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol (M + NH₃)⁺(2S,3R,4R,5S)-2-[4-Chloro-3-(4-methoxy-phenylsulfanyl)- C₁₉H₂₁ClO₆S 430phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S)-2-[4-Chloro-3-(4-methoxy- C₁₉H₂₁ClO₇S 429benzenesulfinyl)-phenyl]-6-methoxy-tetrahydro-pyran- 3,4,5-triol(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₃H₂₉ClO₇ 452.26-(3-hydroxy-propoxy)-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₇ClO₆S 472phenyl]-6-(2-hydroxy-ethylsulfanyl)-tetrahydro-pyran- (M + NH₃)⁺3,4,5-triol* (2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-C₂₂H₂₇ClO₆S 456.3 6-(2-mercapto-ethoxy)-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₃H₂₉ClO₈ 468.26-(2,3-dihydroxy-propoxy)-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(2-methoxy-ethoxy)- C₂₂H₂₇ClO₇ 456benzyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₇ClO₅S 456phenyl]-6-ethylsulfanyl-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₁H₂₅ClO₅S 442phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺[2-Chloro-5-((2S,3R,4R,5S,6S)-3,4,5-trihydroxy-6- C₂₁H₂₃ClO₇ 423methoxy-tetrahydro-pyran-2-yl)-phenyl]-(4-ethoxy- phenyl)-methanone*(2S,3R,4R,5S,6S)-2-{4-Chloro-3-[(4-ethoxy-phenyl)- C₂₁H₂₅ClO₇ 407hydroxy-methyl]-phenyl}-6-methoxy-tetrahydro-pyran- 3,4,5-triol*(2S,3R,4R,5S)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]- C₂₂H₂₈O₆ 4066-methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(2-methylsulfanyl- C₂₂H₂₇ClO₆S 472ethoxy)-benzyl]-phenyl}-6-methoxy-tetrahydro-pyran- (M + NH₃)⁺3,4,5-triol* (2S,3R,4R,5S)-2-{4-Chloro-3-[4-(pyridin-4-yloxy)-C₂₄H₂₄ClNO₆ 458 benzyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S,6S)-2-(4-Chloro-3-{(4-ethoxy-phenyl)-[(Z)- C₂₄H₃₀ClNO₆ 464propylimino]-methyl}-phenyl)-6-methoxy-tetrahydro- pyran-3,4,5-triol(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(thiazol-2-yloxy)- C₂₂H₂₂ClNO₆S 464benzyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(pyrimidin-5-yloxy)- C₂₃H₂₃ClN₂O₆ 459benzyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(2,6-dimethoxy- C₂₅H₂₇ClN₂O₈ 519pyrimidin-4-yloxy)-benzyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol*2-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₆ClNO₆S 468.1phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylsulfanyl}- acetamide*(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₅H₂₇ClO₆S 490.1phenyl]-6-(furan-2-ylmethylsulfanyl)-tetrahydro-pyran- 3,4,5-triol*(2S,3R,4R,5S,6S)-2-{4-Chloro-3-[(4-ethoxy-phenyl)- C₂₁H₂₄ClNO₆ 422imino-methyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5- triol(2S,3R,4R,5S,6S)-2-{3-[(4-Ethoxy-phenyl)-hydroxy- C₂₁H₂₆O₇ 390methyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₈H₃₀ClNO₆ 5113,4,5-trihydroxy-piperidine-1-carboxylic acid benzyl ester(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₄H₂₉ClN₂O₅ 4613,4,5-trihydroxy-piperidine-1-carboxylic acid allylamide*N-(2-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy- C₂₄H₃₀ClNO₆S 496.1benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylsulfanyl}-ethyl)-acetamide*(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₄ClF₃O₅S 492.1phenyl]-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran- 3,4,5-triol*(2S,3R,4R,5S,6S)-2-{4-Chloro-3-[1-(4-ethoxy-phenyl)-1- C₂₂H₂₇ClO₇ 438hydroxy-ethyl]-phenyl}-6-methoxy-tetrahydro-pyran- 3,4,5-triolDimethyl-thiocarbamic acid O-{4-[2-chloro-5- C₂₂H₂₆ClNO₆S 468((2S,3R,4R,5S)-3,4,5-trihydroxy-6-methoxy-tetrahydro-pyran-2-yl)-benzyl]-phenyl} ester*(2S,3R,4R,5S,6S)-2-{3-[1-(4-Ethoxy-phenyl)-ethyl]- C₂₂H₂₈O₆ 406phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol (M + NH₃)⁺Diethyl-dithiocarbamic acid (2R,3S,4R,5R,6S)-6-[4- C₂₅H₃₂ClNO₅S₂ 526.2chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yl ester(2S,3R,4R,5S,6S)-2-(4-Chloro-3-{4-[(R)-(tetrahydro- C₂₃H₂₇ClO₇ 468furan-3-yl)oxy]-benzyl}-phenyl)-6-methoxy-tetrahydro- (M + NH₃)⁺pyran-3,4,5-triol* (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-C₂₂H₂₇ClO₆S 455 phenyl]-6-ethanesulfinyl-tetrahydro-pyran-3,4,5-triol*(2S,3R,4R,5S)-2-{4-Chloro-3-[4-((S)-1-methyl-pyrrolidin- C₂₄H₃₀ClNO₆ 5223-yloxy)-benzyl]-phenyl}-6-methoxy-tetrahydro-pyran- (M − H + Ac)3,4,5-triol* (2S,3R,4R,5S)-2-{4-Chloro-3-[4-(tetrahydro-pyran-4-C₂₄H₂₉ClO₇ 523 yloxy)-benzyl]-phenyl}-6-methoxy-tetrahydro-pyran- (M −H + Ac) 3,4,5-triol* (2S,3R,4R,5S)-2-(4-Chloro-3-{4-hydroxy-3-[1-(2-C₂₅H₃₂ClNO₆ 478 methylamino-ethyl)-allyl]-benzyl}-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(1-methyl-piperidin-4- C₂₅H₃₂ClNO₆ 478yloxy)-benzyl]-phenyl}-6-methoxy-tetrahydro-pyran- 3,4,5-triol*(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₁H₂₅ClO₆S 441phenyl]-6-methanesulfinyl-tetrahydro-pyran-3,4,5-triol*(2S,3S,4S,5R)-1-Benzyl-2-[4-chloro-3-(4-ethoxy-benzyl)- C₂₇H₃₀ClNO₄ 468phenyl]-piperidine-3,4,5-triol*(2S,3R,4R,5S)-2-{3-[4-(2-Benzyloxy-ethoxy)-benzyl]-4- C₂₈H₃₁ClO₇ 532chloro-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S)-2-{3-[4-(2-Hydroxy-ethoxy)-benzyl]- C₂₁H₂₆O₇ 408phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺(2S,3R,4R,5S)-2-{4-Chloro-3-[4-(2-hydroxy-ethoxy)- C₂₁H₂₅ClO₇ 442benzyl]-phenyl}-6-methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺2-{(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₇ClN₂O₅ 435phenyl]-3,4,5-trihydroxy-piperidin-1-yl}-acetamide*(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₄H₃₂ClNO₄ 4921-isobutyl-piperidine-3,4,5-triol* (M − H + Ac)(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₅H₃₁ClO₆S 512phenyl]-6-(2-methyl-tetrahydro-furan-3-ylsulfanyl)- (M + NH₃)⁺tetrahydro-pyran-3,4,5-triol*(R)-2-Amino-3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4- C₂₃H₂₈ClNO₇S 498ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylsulfanyl}-propionic acid*(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₅H₃₁ClO₅S 496phenyl]-6-cyclopentylsulfanyl-tetrahydro-pyran-3,4,5- (M + NH₃)⁺ triol*(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₆H₃₃ClO₅S 510phenyl]-6-cyclohexylsulfanyl-tetrahydro-pyran-3,4,5-triol (M + NH₃)⁺(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₅H₃₃ClO₅S 498phenyl]-6-(3-methyl-butylsulfanyl)-tetrahydro-pyran- (M + NH₃)⁺3,4,5-triol* (2S,3R,4R,5S)-2-[3-(4-Ethoxy-benzyl)-phenyl]-6- C₂₇H₃₁ClO₉552 methoxy-tetrahydro-pyran-3,4,5-triol* (M + NH₃)⁺1-{(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₆ClNO₅ 420phenyl]-3,4,5-trihydroxy-piperidin-1-yl}-ethanone*(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₈H₃₀ClNO₆ 5293,4,5-trihydroxy-piperidine-1-carboxylic acid benzyl ester [M + NH₄]+(2S,3S,4S,5R)-1-Benzyl-2-[4-chloro-3-(4-ethoxy-benzyl)- C₂₇H₃₀ClNO₄ 468phenyl]-piperidine-3,4,5-triol*2-{(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)- C₂₂H₂₇ClN₂O₅ 435phenyl]-3,4,5-trihydroxy-piperidin-1-yl}-acetamide*(2S,3S,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]- C₂₄H₃₂ClNO₄ 4921-isobutyl-piperidine-3,4,5-triol* [M + Ac]⁻(3S,4R,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6- C₂₁H₂₆ClNO₅ 408hydroxymethyl-piperidine-3,4,5-triol*

6.25. In Vitro Human SGLT2 Inhibition Assay

Human sodium/glucose co-transporter type 2 (SGLT2; accession numberP31639; GI:400337) was cloned into pIRESpuro2 vector for mammalianexpression (construct: HA-SGLT2-pIRESpuro2).

HEK293 cells were transfected with the human HA-SGLT2-pIRESpuro2 vectorand the bulk stable cell line was selected in presence of 0.5 μg/ml ofpuromycin. Human HA-SGLT2 cells were maintained in DMEM media containing10% FBS, 1% GPS and 0.5 μg/ml of puromycin.

The HEK293 cells expressing the human HA-SGLT2 were seeded in 384 wellplates (30,000 cells/well) in DMEM media containing 10% FBS, 1% GPS and0.5 μg/ml of puromycin, then incubated overnight at 37 C, 5% CO₂. Cellswere then washed with uptake buffer (140 mM NaCl, 2 mM KCl, 1 mM CaCl₂,1 mM MgCl₂, 10 mM HEPES, 5 mM Tris, 1 mg/ml bovine serum albumin (BSA),pH 7.3). Twenty microliters of uptake buffer with or without testingcompounds were added to the cells. Then, 20 microliters of uptake buffercontaining ¹⁴C-AMG (100 nCi) were added to the cells. The cell plateswere incubated at 37° C., 5% CO₂ for 1-2 hours. After washing the cellswith uptake buffer, scintillation fluid was added (40 microliters/well)and ¹⁴C-AMG uptake was measured by counting radioactivity using ascintillation coulter (TopCoulter NXT; Packard Instruments).

6.26. In Vitro Human SGLT1 Inhibition Assay

Human sodium/glucose co-transporter type 1 (SGLT1; accession numberNP_(—)000334; GI: 4507031) was cloned into pIRESpuro2 vector formammalian expression (construct: HA-SGLT1-pIRESpuro2).

HEK293 cells were transfected with the human HA-SGLT1-pIRESpuro2 vectorand the bulk stable cell line was selected in presence of 0.5 μg/ml ofpuromycin. Human HA-SGLT1 cells were maintained in DMEM media containing10% FBS, 1% GPS and 0.5 μg/ml of puromycin.

The HEK293 cells expressing the human HA-SGLT1 were seeded in 384 wellplates (30,000 cells/well) in DMEM media containing 10% FBS, 1% GPS and0.5 μg/ml of puromycin, then incubated overnight at 37 C, 5% CO₂. Cellswere then washed with uptake buffer (140 mM NaCl, 2 mM KCl, 1 mM CaCl₂,1 mM MgCl₂, 10 mM HEPES, 5 mM Tris, 1 mg/ml bovine serum albumin (BSA),pH 7.3). Twenty microliters of uptake buffer with or without testingcompounds were added to the cells. Then, 20 microliters of uptake buffercontaining ¹⁴C-AMG (100 nCi) were also added to cells. The cell plateswere incubated at 37° C., 5% CO₂ for 1-2 hours. After washing the cellswith uptake buffer, scintillation fluid was added (40 microliters/well)and ¹⁴C-AMG uptake was measured by counting radioactivity using ascintillation coulter (TopCoulter NXT; Packard Instruments).

6.27. Calculating IC₅₀ Values

The IC₅₀ of a compound with regard to a given target is determined byfitting the relevant data, using the Levenburg Marquardt algorithm, tothe equation:

y=A+((B−A)/(1+((C/x)̂D)))

wherein A is the minimum y value; B is the maximum y value; C is theIC₅₀; and D is the slope. The calculation of the IC₅₀ is performed usingXLFit4 software (ID Business Solutions Inc., Bridgewater, N.J. 08807)for Microsoft Excel (the above equation is model 205 of that software).

6.28. In Vivo Effect of Compounds

The pharmacological effects of compounds of the invention was determinedusing six drug-treated and six vehicle-treated c57 albino male miceweaned on 45% high fat diet and individually-housed in a Nalgenemetabolic cage. The mice were provided drinking water and high-fat dietpaste (2 parts diet to 1 part water) ad libitum.

Compounds were delivered two ways. In the first, mice were gavaged withdrug or vehicle on day 1 with 5 ml/kg dose volume. The entire urinevolume was collected for the following 24 hours into the metabolic cageplastic urine collector. Measures of mouse body weight, waterconsumption, food consumption (accounting for evaporation of water inthe paste), and urine volume were made daily. Urine was collected daily,centrifuged, and assessed for glucose concentration using a CobasAutoanalyzer. The final result of milligrams of glucose excreted per daywas calculated from total urine volume and urine glucose concentration.

In the second method, compounds were delivered in the diet. This wasdone by mixing the test compound in the high fat diet paste at theappropriate concentration, when taking into account baseline body weightand baseline food consumption. Paste containing the drug was againprovided in excess each day. The amount of compound delivered per daywas confirmed by calculating animal body weight and food consumption.

FIG. 1 shows the effect of four compounds of the invention (A, B, C andD), when orally dosed once at 30 mg/kg, on the amount of excretedglucose during the 24 hours following dosing. By comparison, controlanimals excreted about 1 mg glucose over the 24 hours.

All publications (e.g., patents and patent applications) cited above areincorporated herein by reference in their entireties.

1-290. (canceled)
 291. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is optionallysubstituted aryl, cycloalkyl, or heterocycle; B is optionallysubstituted aryl, cycloalkyl, or heterocycle; Y is O, S, SO, SO₂, NR₄,(C(R₅)₂)_(p), (C(R₅)₂)_(q)—C(O)—(C(R₅)₂)_(q),(C(R₅)₂)_(q)—C(O)O—(C(R₅)₂)_(q), (C(R₅)₂)_(q)—OC(O)—(C(R₅)₂)_(q),(C(R₅)₂)_(q)—C(O)NR₄—(C(R₅)₂)_(q), (C(R₅)₂)_(q)—NR₄C(O)—(C(R₅)₂)_(q), or(C(R₅)₂)_(q)—NC(O)NR₄—(C(R₅)₂)_(q); R₁ is OR_(1A), SR_(1A), SOR_(1A),SO₂R_(1A), or R_(1A); each R_(1A) is independently hydrogen oroptionally substituted alkyl, aryl or heterocycle; R₂ is fluoro orOR_(2A); R₃ is hydrogen or optionally substituted alkyl, aryl orheterocycle; each of R_(2A), R_(2B), and R_(2C) is independentlyhydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl, or aryl;each R₄ is independently hydrogen or optionally substituted alkyl; eachR₅ is independently hydrogen, hydroxyl, halogen, amino, cyano, OR_(5A),SR_(5A), or optionally substituted alkyl; each R_(5A) is independentlyoptionally substituted alkyl; p is 0-3; and each q is independently 0-2.292. The compound of claim 291, which is of the formula:


293. The compound of claim 292, which is of the formula:


294. The compound of claim 293, which is of the formula:


295. The compound of claim 294, which is of the formula:

wherein: each R₆ is independently hydrogen, hydroxyl, halogen, amino,cyano, nitro, C≡CR_(6A), OR_(6A), SR_(6A), SOR_(6A), SO₂R_(6A),C(O)R_(6A), CO₂R_(6A), CO₂H, CON(R_(6A))(R_(6A)), CONH(R_(6A)), CONH₂,NHC(O)R_(6A), NHSO₂R_(6A), or optionally substituted alkyl, aryl orheterocycle; each R_(6A) is independently optionally substituted alkyl,aryl or heterocycle; each R₇ is independently hydrogen, hydroxyl,halogen, amino, cyano, nitro, C≡CR_(7A), OR_(7A), SR_(7A), SOR_(7A),SO₂R_(7A), C(O)R_(7A), CO₂R_(7A), CO₂H, CON(R_(7A))(R_(7A)),CONH(R_(7A)), CONH₂, NHC(O)R_(7A), NHSO₂R_(7A), or optionallysubstituted alkyl, aryl or heterocycle; each R_(7A) is independentlyoptionally substituted alkyl, aryl or heterocycle; m is 1-3; and n is1-3.
 296. The compound of claim 295, which is of the formula:


297. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: R₁ is OR_(1A),SR_(1A), SOR_(1A), SO₂R_(1A), or R_(1A); each R_(1A) is independentlyhydrogen or optionally substituted alkyl, aryl or heterocycle; R₂ isfluoro or OR_(2A); each R_(2A) is independently hydrogen, optionallysubstituted alkyl, C(O)alkyl, C(O)aryl, or aryl; each R₆ isindependently hydrogen, hydroxyl, halogen, amino, cyano, nitro,C≡CR_(6A), OR_(6A), SR_(6A), SOR_(6A), SO₂R_(6A), C(O)R_(6A), CO₂R_(6A),CO₂H, CON(R_(6A))(R_(6A)), CONH(R_(6A)), CONH₂, NHC(O)R_(6A),NHSO₂R_(6A), or optionally substituted alkyl, aryl or heterocycle; eachR_(6A) is independently optionally substituted alkyl, aryl orheterocycle; each R₇ is independently hydrogen, hydroxyl, halogen,amino, cyano, nitro, C≡CR_(7A), OR_(7A), SR_(7A), SOR_(7A), SO₂R_(7A),C(O)R_(7A), CO₂R_(7A), CO₂H, CON(R_(7A))(R_(7A)), CONH(R_(7A)), CONH₂,NHC(O)R_(7A), NHSO₂R_(7A), or optionally substituted alkyl, aryl orheterocycle; each R_(7A) is independently optionally substituted alkyl,aryl or heterocycle; m is 1-3; and n is 1-3.
 298. The compound of claim297, wherein R₁ is OR_(1A).
 299. The compound of claim 298, whereinR_(1A) is hydrogen.
 300. The compound of claim 298, wherein R_(1A) isoptionally substituted alkyl.
 301. The compound of claim 297, wherein R₁is SR_(1A).
 302. The compound of claim 301, wherein R_(1A) is hydrogen.303. The compound of claim 301, wherein R_(1A) is optionally substitutedalkyl.
 304. The compound of claim 297, wherein R₁ is SOR_(1A).
 305. Thecompound of claim 304, wherein R_(1A) is hydrogen.
 306. The compound ofclaim 304, wherein R_(1A) is optionally substituted alkyl.
 307. Thecompound of claim 297, wherein R₁ is SO₂R_(1A).
 308. The compound ofclaim 307, wherein R_(1A) is hydrogen.
 309. The compound of claim 307,wherein R_(1A) is optionally substituted alkyl.
 310. The compound ofclaim 297, wherein R₁ is N(R_(1A))₂.
 311. The compound of claim 310,wherein at least one R_(1A) is hydrogen.
 312. The compound of claim 310,wherein at least one R_(1A) is optionally substituted alkyl.
 313. Thecompound of claim 297, wherein R₁ is R_(1A).
 314. The compound of claim313, wherein R_(1A) is hydrogen.
 315. The compound of claim 313, whereinR_(1A) is optionally substituted alkyl.
 316. The compound of claim 297,wherein R₆ is hydrogen, hydroxyl, halogen, OR_(6A) or optionallysubstituted lower alkyl.
 317. The compound of claim 316, wherein R₆ ishydrogen.
 318. The compound of claim 316, wherein R₆ is halogen. 319.The compound of claim 316, wherein R₆ is hydroxyl.
 320. The compound ofclaim 316, wherein R₆ is OR_(6A).
 321. The compound of claim 316,wherein R₆ is optionally substituted methyl.
 322. The compound of claim297, wherein R₇ is hydrogen, C≡CR_(7A), OR_(7A) or optionallysubstituted lower alkyl.
 323. The compound of claim 322, wherein R₇ ishydrogen.
 324. The compound of claim 322, wherein R₇ is C≡CR_(7A). 325.The compound of claim 322, wherein R₇ is OR_(7A).
 326. A method oftreating or managing a disease or disorder in a patient, which comprisesadministering to a patient in need thereof a therapeutically orprophylactically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: the disease ordisorder is atherosclerosis, cardiovascular disease, diabetes,hyperglycemia, hypertension, lipid disorders, obesity, or Syndrome X; Ais optionally substituted aryl, cycloalkyl, or heterocycle; B isoptionally substituted aryl, cycloalkyl, or heterocycle; Y is O, S, SO,SO₂, NR₄, (C(R₅)₂)_(p), (C(R₅)₂)_(q)—C(O)—(C(R₅)₂)_(q),(C(R₅)₂)_(q)—C(O)O—(C(R₅)₂)_(q), (C(R₅)₂)_(q)—OC(O)—(C(R₅)₂)_(q),(C(R₅)₂)_(q)—C(O)NR₄—(C(R₅)₂)_(q), (C(R₅)₂)_(q)—NR₄C(O)—(C(R₅)₂)_(q), or(C(R₅)₂)_(q)—NR₄C(O)NR₄—(C(R₅)₂)_(q); R₁ is OR_(1A), SR_(1A), SOR_(1A),SO₂R_(1A), or R_(1A); each R_(1A) is independently hydrogen oroptionally substituted alkyl, aryl or heterocycle; R₂ is fluoro orOR_(2A); R₃ is hydrogen or optionally substituted alkyl, aryl orheterocycle; each of R_(2A), R_(2B), and R_(2C) is independentlyhydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl, or aryl;each R₄ is independently hydrogen or optionally substituted alkyl; eachR₅ is independently hydrogen, hydroxyl, halogen, amino, cyano, OR_(5A),SR_(5A), or optionally substituted alkyl; each R_(5A) is independentlyoptionally substituted alkyl; p is 0-3; and each q is independently 0-2.327. The method of claim 326, wherein the disease or disorder is type 2diabetes.